As readers of this Substack know, I have maintained that SPED (Spike Protein Endothelial Disease) is just an early step in the Spike Protein’s systemic assault on the body. Today we can move this hypothesis forward with a look at a more advanced stage of what I will call Systemic Spike Protein Disease (SSPD). This stage I will call The Spike Feed-Forward Loop. The origins of this stage stem from the following questions:

What if Spike Protein does more than damage the endothelium? What if it actually prepares the vascular environment for the macrophages that carry it?

Of course, the endothelium is not simply a passive lining. When it becomes activated or dysfunctional, it changes dramatically. It can increase adhesion molecules and inflammatory signals that allow circulating immune cells to slow down, adhere to the vessel wall and ultimately migrate through it, invading tissues and organs.

And this raises a fascinating possibility in the context of persistent Spike.

Spike → endothelial dysfunction → increased leukocyte adhesion → macrophage recruitment → macrophage adhesion/invasion → further vascular injury.

In this model, endothelial dysfunction isn’t merely a consequence of Spike exposure.

It could be part of the mechanism that allows Spike-laden macrophages to gain access to the tissues and organs beneath the endothelium.

Let’s look at the evidence.

The Spike Protein Activates the Endothelium

Having an activated endothelium to attract Spike-laden macrophages is the foundation of the entire process.

COVID-19 has been associated with an active immunothrombotic process. The involvement of endothelial cells (ECs) in the feedback loop of the inflammatory and thrombotic process characteristic of COVID-19, as well as its differences with other infectious inflammatory conditions, remains an area requiring further elucidation. This study aimed to assess the immunothrombotic phenotype induced by the SARS-CoV-2 Spike (S) protein and its receptor-binding domain (RBD) in endothelial-derived cell lines. HUVEC and EA.hy926 cell lines were exposed to S protein and to its RBD. Inflammatory, thrombotic, and fibrinolytic mediators were quantified. Molecular docking assays were conducted to identify potential EC receptors for S protein. EC activation was dependent on both protein concentration and stimulation time.

Endothelial Cell Activation by SARS-CoV-2 Spike Protein and Its RBD: Central Player of the Immunothrobotic Response in COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC12939624/

Macrophage Infiltration in Those with Long COVID

Next, there is evidence that macrophages are infiltrating tissues in people with Long COVID, in association with substantial microvascular abnormalities.

The SARS-CoV-2 pandemic not only resulted in millions of acute infections worldwide, but also caused innumerable cases of post-infectious syndromes, colloquially referred to as “long COVID”. Due to the heterogeneous nature of symptoms and scarcity of available tissue samples, little is known about the underlying mechanisms. We present an in-depth analysis of skeletal muscle biopsies obtained from eleven patients suffering from enduring fatigue and post-exertional malaise after an infection with SARS-CoV-2. Compared to two independent historical control cohorts, patients with post-COVID exertion intolerance had fewer capillaries, thicker capillary basement membranes and increased numbers of CD169+ macrophages.

Post-COVID syndrome is associated with capillary alterations, macrophage infiltration and distinct transcriptomic signatures in skeletal muscles
https://www.medrxiv.org/content/10.1101/2023.02.15.23285584v1.full-text

Spike Protein Persists for a Long Time in Macrophages

The third pillar of this hypothesis is the required presence of Spike-laden macrophages to initiate and maintain the feed-forward loop. There is evidence that Spike does persist for a very long time in macrophages.

Macrophages play a central role in immune regulation, inflammation, and tissue repair, and exist in phenotypically distinct subtypes derived from circulating monocytes: classical (CD14+, CD16−), intermediate (CD14+, CD16+), and non-classical (CD14lo, CD16+). Intermediate and non-classical monocytes express high levels of CCR5 and CX3CR1, which promotes their migration to and retention within previously inflamed tissues and vasculature [11,15]. In Long COVID, macrophage hyperactivation appears to be a core mechanism of disease, especially in an environment where active inflammation is already present. Intermediate and non-classical monocytes have been shown to harbor SARS-CoV-2 S1 protein for up to 15 months post-infection, despite an absence of full-length viral RNA, indicating persistent antigenic stimulation [11]. These cells are associated with elevated levels of inflammatory cytokines such as IL-6, CCL5, and sCD40L, as well as platelet and endothelial activation, which are characteristic features of PASC [1].

The Central Role of Macrophages in Long COVID Pathophysiology
https://www.mdpi.com/1422-0067/27/1/313

Studying these elements together logically leads to the feed-forward loop hypothesis discussed earlier:

Spike → endothelial dysfunction → increased leukocyte adhesion → macrophage recruitment → macrophage adhesion/invasion → further vascular injury.

Of course, there is an important distinction between assembling these observations into a mechanistic hypothesis and demonstrating the entire pathway experimentally. We have not yet shown that Spike-induced endothelial activation specifically causes Spike-bearing macrophages to adhere and transmigrate into tissue. That is precisely the question I believe now needs to be tested.

Now to conduct studies where we seek to discover under what conditions this feed forward loop may establish itself. The source of the Spike Proteins involved needs to be determined as well. It is my hope that this will lead to further understanding of and the development of effective therapeutics for Long COVID.

Thank you, as always, for your readership, dialogue and support. We gained two new paid subscribers, and three people made generous one-time donations since Friday. Please have a blessed week.

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Piperine—the pungent natural compound that gives black pepper its bite—may have something particularly interesting to offer in the fight against COVID and the chronic inflammatory aftermath that can follow it.

For those of us interested in the role of persistently activated macrophages, that is where the story becomes especially compelling.

First, let’s talk more about what Piperine is – and the long therapeutic history it has.

Piper nigrum Linn, belonging to the Piperaceae family, is mainly cultivated for its fruits in Malaysia, Vietnam, China, and other countries [1]. P. nigrum is a traditional dual-use resource of medicine and food resources in China, while traditionally it can be used for treating chills, stomach, detoxification and rheumatism [2]. Piperine is the major active compound in both white and black pepper. Several studies have indicated that piperine has various biological functions, including immune enhancement [3], anti-cancer [4], anti-inflammatory [5], antioxidant [6], and antibacterial activities [7,8]. Due to its biological activity, the application of piperine has increased globally in the past couple of years.

Piperine Derived from Piper nigrum L. Inhibits LPS-Induced Inflammatory through the MAPK and NF-κB Signalling Pathways in RAW264.7 Cells
https://www.mdpi.com/2304-8158/11/19/2990

Piperine May Help Ameliorate Acute COVID Symptoms

There is some evidence that Piperine may help with acute COVID symptoms. In a randomized trial of COVID patients, curcumin plus piperine showed early symptomatic recovery and reduced duration of hospitalization time.

Results: Patients with mild, moderate, and severe symptoms who received curcumin/piperine treatment showed early symptomatic recovery (fever, cough, sore throat, and breathlessness), less deterioration, fewer red flag signs, better ability to maintain oxygen saturation above 94% on room air, and better clinical outcomes compared to patients of the control group. Furthermore, curcumin/piperine treatment appeared to reduce the duration of hospitalization in patients with moderate to severe symptoms, and fewer deaths were observed in the curcumin/piperine treatment group.

Conclusions: Administration of oral curcumin with piperine as an adjuvant symptomatic therapy in COVID-19 treatment could substantially reduce morbidity and mortality, and ease the logistical and supply-related burdens on the healthcare system. Curcumin could be a safe and natural therapeutic option to prevent Post-Covid thromboembolic events.

Oral Curcumin With Piperine as Adjuvant Therapy for the Treatment of COVID-19: A Randomized Clinical Trial
https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.669362/full

But perhaps the most intriguing part of the story is not how piperine may treat an acute COVID infection.

It is what it may do to the macrophage.

Piperine Appears to Put the Brakes on Overactivated Macrophages

Macrophages are supposed to become activated. They are among the immune system’s first responders. They engulf threats, release inflammatory signals and help coordinate the immune response.

The problem comes when they do not turn off.

That is one of the central ideas behind what I have been calling Smoldering Macrophage Syndrome: macrophages may continue producing inflammatory mediators, damaging surrounding tissues and sustaining a pathological feedback loop long after the initial infection has passed, driven by persistent viral material (Spike).

Recent research makes piperine particularly interesting here.

A new study found that piperine suppressed the pro-inflammatory M1 phenotype in activated macrophages. It reduced iNOS and nitric oxide and suppressed pro-inflammatory mediators including IL-1β, TNF-α and IFN-γ.

Piperine dose-dependently decreased iNOS gene expression and NO level in LPS-stimulated macrophages. Additionally, at concentrations of 1–20 µg/ml, it significantly suppressed the production and/or gene expression levels of proinflammatory M1-related cytokines. Its effects on cytokine genes were dose-dependent, and reduced IL-1β, TNF-α, and IFN-γ expression (17 ± 11.8, 1.33 ± 0.76, and 25.4 ± 5.2 fold, respectively, compared with LPS-stimulated cells). Piperine at 1 µg/ml didn’t affect the IL-10 gene but significantly increased IDO1 (from 8.4 ± 0.24-fold in LPS-treated cells to 28.3 ± 5.3-fold in piperine-treated cells), and decreased IL-4 gene expressions at the higher concentrations. Dexamethasone (a glucocorticoid anti-inflammatory drug) reduced most mediators but did not affect the IDO gene. Our data demonstrate that piperine dose-dependently inhibits M1-macrophages and upregulates IDO1 at low concentration, a unique mechanism of action, positioning it as a multifaceted therapeutic candidate for inflammatory conditions.

Piperine suppresses M1 phenotype and induces indoleamine 2,3-dioxygenase gene in LPS-stimulated murine macrophage cell line
https://pmc.ncbi.nlm.nih.gov/articles/PMC12613537/

I have always enjoyed heavily peppered eggs, soups and mashed potatoes. It’s good to know that these peppered delights are doing far more than tantalizing the taste buds! I would like to thank everyone for the wonderful response this week to the Semi-Annual Appear. We gained six new paid subscribers, and several people made generous one-time donations. Thank you, as well and as always, for your readership, dialogue and support. Please have a blessed weekend.

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I want to be candid with you.

We now have more than 13,500 subscribers in our community. That is something I never take for granted. I am deeply grateful that so many people have chosen to follow this work, read these posts, and join me in asking difficult questions about Long COVID and chronic disease.

But there is another number I need to share.

We currently have just 332 paid subscribers.

That means only about 2.4% of our 13,750 subscribers are paid supporters—and more than 97% are receiving this work for free.

Since May, I have actually lost about 10% of our paid subscribers, falling from 363 to 332. I understand that times are tough. Budgets are tight, subscriptions add up, and there are many competing demands on people’s resources.

But I also need to be honest about what this means for me.

My sustainable goal is 700 paid subscribers. At 332, I am still less than halfway there—and we need 368 more paid supporters to reach that goal.

The remarkable thing is that we don’t need thousands of people to step up.

With 13,750 people following this work, if even a small additional percentage of free subscribers decided it was worth supporting, we could reach that goal.

And I believe the work is becoming more important, not less.

Over the past months, we have explored persistent Spike protein, macrophages as potential carriers, endothelial and microvascular dysfunction, foam-cell arteriopathy, immune dysregulation, molecular mimicry, FcγRIIB, HLA, fibrosis, and many other possible pieces of the Long COVID puzzle.

This is what independent research allows me to do: to follow the evidence, connect findings across scientific silos, and ask questions that may not fit neatly into existing frameworks.

I believe some of our most important discoveries may still be ahead.

But I cannot pretend that this work does not require support. The research, reading, writing, journal subscriptions and investigation take an enormous amount of time. Paid subscriptions are what make it possible for me to continue devoting that time to this work.

So this is my semi-annual appeal.

If you are one of the more than 13,750 people receiving these posts and you have found value in them, please consider becoming a paid subscriber. If you already support this work, thank you. You are carrying far more of the burden than you should have to.

And if you cannot subscribe, sharing this work with someone who might value it is another enormous help.

I know 700 paid subscribers is an ambitious goal.

But with a community of more than 13,750 people, I don’t believe it is impossible.

I need just 368 more people who believe this work is worth supporting.

If you believe in independent research, intellectual curiosity, connecting dots that others may overlook, and continuing to search for answers to one of the greatest medical mysteries of our time, I hope you will consider helping me get there.

Thank you—for reading, questioning, sharing, and supporting this work. Blessings always.

Walter

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So many people have asked, “Why wait until Monday to read this?” I have been working on this post continuously and finished it this morning. I agree with them. It is complete - why wait? I am publishing Monday’s post early for those who made the request.

One of the enduring mysteries of Long COVID is how a respiratory virus can produce such a remarkably systemic disease. Why does persistent viral material (Spike Protein) appear to be associated with pathology in the heart, brain, gut, vasculature, adipose tissue and other distant organs?

We tend to imagine the virus—or Spike Protein—as something that simply spreads through the body. But we seem to ignore the most important question:

What is carrying it?

A potentially revolutionary way of looking at Long COVID may come from an unlikely field: cancer metastasis.

The metastatic cancer cell and the Spike-laden macrophage

Metastatic cancer cells do not simply drift randomly through the body.

They must adhere, migrate, interact with the extracellular matrix, cross biological barriers, enter distant tissues and establish themselves in a new microenvironment. Integrins play a central role in many of these processes.

Recently, emerging evidence has revealed that integrins expressed on the surface of exosomes can guide tumor-derived exosomes to specific metastatic organs (Soe et al., 2021). Tumor exosomes expressing α6β1 and α6β4 are linked to liver metastasis, while exosomal αvβ3 and αvβ5 integrin are associated with prostate and lung metastasis, respectively (Hoshino et al., 2015; Krishn et al., 2019). Moreover, inhibition of αvβ5 and α6β4 integrin can lead to suppression of liver and lung metastasis, respectively (Hoshino et al., 2015). In addition, exosomal α6β4 was reported to activate fibroblasts by upregulating S100 and activating SRC signaling (Hoshino et al., 2015). All these observations suggest that integrins on the surface of exosomes are important for cell adhesion and migration and have vital roles in the immune microenvironment (Casari et al., 2021; Ellert-Miklaszewska, Poleszak, Pasierbinska, & Kaminska, 2020; Soe et al., 2021). Taken together, these findings indicate that exosomal integrins have vital functions in cancer cell invasion and migration. Therefore, identifying and targeting exosomal integrins is an important strategy for overcoming tumor metastasis.

Integrins in cancer: Emerging mechanisms and therapeutic opportunities
https://www.sciencedirect.com/science/article/pii/S0163725823001225

But macrophages are also highly mobile cells.

They express integrins and other adhesion molecules that allow them to interact with the extracellular matrix and vascular endothelium, migrate along chemokine gradients, cross tissue barriers and enter organs throughout the body and are critical in cancer metastasis independent of SARS-CoV-2 viral RNA.

Lymphatic vasculature is crucial for metastasis in triple-negative breast cancer (TNBC); however, cellular and molecular drivers controlling lymphovascular metastasis are poorly understood. We define a macrophage-dependent signaling cascade that facilitates metastasis through lymphovascular remodeling. TNBC cells instigate mRNA changes in macrophages, resulting in β4 integrin-dependent adhesion to the lymphovasculature. β4 integrin retains macrophages proximal to lymphatic endothelial cells (LECs), where release of TGF-β1 drives LEC contraction via RhoA activation. Macrophages promote gross architectural changes to lymphovasculature by increasing dilation, hyperpermeability, and disorganization. TGF-β1 drives β4 integrin clustering at the macrophage plasma membrane, further promoting macrophage adhesion and demonstrating the dual functionality of TGF-β1 signaling in this context. β4 integrin-expressing macrophages were identified in human breast tumors, and a combination of vascular-remodeling macrophage gene signature and TGF-β signaling scores correlates with metastasis. We postulate that future clinical strategies for patients with TNBC should target crosstalk between β4 integrin and TGF-β1.

Integrin-Mediated Macrophage Adhesion Promotes Lymphovascular Dissemination in Breast Cancer
https://pmc.ncbi.nlm.nih.gov/articles/PMC6527923/

This raises a provocative possibility.

What if a macrophage carrying persistent SARS-CoV-2 material—including Spike protein—functions as a cellular vehicle for systemic dissemination?

Not a metastatic cancer cell. But potentially using parallel biological machinery.

The parallel

Metastatic cancer cells use adhesion and invasion mechanisms to disseminate:

Adhesion → migration → vascular interaction → tissue entry → establishment in a new microenvironment.

A Spike-laden macrophage could potentially follow a strikingly similar path:

Spike persistence → macrophage activation → altered adhesion and trafficking → vascular interaction → tissue infiltration → local inflammatory pathology.

The important difference is the cargo. The cancer cell carries its own malignant program. The macrophage may carry persistent viral material (Spike Protein) capable of continually stimulating the cell itself—and potentially the tissue in which it arrives.

A mobile reservoir

This may fundamentally change how we think about viral persistence. Perhaps the most important reservoir is not always a fixed anatomical location.

Perhaps, in some cases, it is mobile.

A macrophage containing persistent Spike or other viral material is uniquely positioned to travel. And wherever it goes, it may potentially carry the consequences of that persistence with it. Once it enters a susceptible tissue, the macrophage could contribute to a local pathological environment through inflammatory cytokines, reactive oxygen species, matrix remodeling enzymes and other mediators.

If Spike remains present, that inflammatory state may be continually reinforced. The result could be a self-perpetuating loop:

Persistent Spike → macrophage activation → tissue trafficking → local inflammation and endothelial injury → recruitment of additional immune cells → further macrophage activation.

It is my hope that looking at Long COVID as an INVASIVE disease will help us understand it more, and find novel ways to treat it. Those who have followed my work over the years know that near the beginning I called Long COVID “Cancer without tumors.” I saw what is was doing. Now we can observe how.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. I would especially like to thank the two individuals who made generous one-time donations over the past week. Please have a blessed week.

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Nattokinase has been widely touted for its proposed ability to remove Spike from our bodies. I would like to propose that it actually does something that may be of equal, or perhaps greater benefit. Nattokinase may help put a full stop to the thromboinflammation and neuropathology in COVID-19. This is why a natural fibrinolytic enzyme such as nattokinase deserves a closer look.

We have known essentially from the beginning that severe COVID-19 (and Long COVID) is associated with coagulation abnormalities, endothelial injury and extensive fibrin deposition. Today I would like to discuss a remarkable 2024 study published in Nature which suggests that fibrin may be much more than a bystander.

The researchers found that SARS-CoV-2 Spike protein binds directly to fibrin and fibrinogen.

Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection.

Fibrin drives thromboinflammation and neuropathology in COVID-19
https://www.nature.com/articles/s41586-024-07873-4

And what happens next is particularly important.

The Spike–fibrin interaction produces pro-inflammatory blood clots that can drive thromboinflammation. Fibrin was shown to contribute to oxidative stress and macrophage activation in the lungs, suppress natural killer-cell responses, and promote neuroinflammation and neuronal injury.

In other words:

Spike + fibrin may create a pathological feedback loop.

This leads to a logical question: What if preserving fibrinolytic (breaking down fibrin) capacity before and during infection could help prevent this cycle from becoming established?

Enter nattokinase.

Nattokinase is a fibrinolytic enzyme produced during the fermentation of soybeans by Bacillus subtilis. Human studies have demonstrated that oral nattokinase can increase markers of fibrinolysis and influence several components of the coagulation system.

One controlled human study found that nattokinase increased D-dimer and fibrin/fibrinogen degradation products while reducing factor VIII activity—evidence that it can shift the hemostatic system toward fibrinolysis.

A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously.

A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles
https://pmc.ncbi.nlm.nih.gov/articles/PMC4479826/

If excessive fibrin is not simply an unfortunate consequence of COVID—but is actually participating in thromboinflammation, macrophage activation, endothelial injury and neurological pathology—then maintaining the ability to efficiently clear fibrin could potentially be protective.

Let’s look at the sequence:

Spike → fibrin binding → inflammatory clot formation → macrophage activation → endothelial injury → microvascular dysfunction

Nattokinase potentially attacks the process from another direction:

Nattokinase → enhanced fibrinolysis → less fibrin substrate → potentially less inflammatory clot burden

Please bear in mind that this hypothesis is NOT proof that nattokinase prevents severe COVID. We need clinical trials specifically testing that question, and I hope that those with labs reading this will endeavor to answer that question. Always consult your primary care provider before using any medication or supplement.

Sometimes the most promising therapeutic target isn’t the pathogen itself—but the pathological process it triggers.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Please have a blessed weekend.

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The presence of human immune cells promotes the dissemination of SARS-CoV-2 and increases viral levels in mouse lung.

a. Schematic of hACE2 KI NSG HIS mouse infection study. A subset of mice also expressed an HLA-A2 transgene. Homozygous hACE2 KI NSG mice were thymectomized and reconstituted with either fetal liver CD34+ HSCs (2x105 cells) alone or both HSCs and a human fetal thymus graft under the kidney capsule or left unreconstituted. After 3-4 months to allow human immune cell reconstitution, mice were intranasally infected with the WA1 strain of SARS-CoV-2 (5x103 pfu) or mock infected with PBS. Tissues were harvested at 7, 14 days, and 8 weeks post-infection. b,c. Reconstitution of human CD45+ cells (b) and human CD3+ T cells (c) in PBMC, lung, and spleen of HIS hACE2 mice at 16-20 weeks post-transplantation, as determined by flow cytometry. Hu/Hu n = 19, Hu n = 21. All displayed p-values < 0.0001. d. Percentage of mice from each infected group demonstrating SARS-CoV-2 spike protein-specific qPCR CT values across multiple tissues. PBS control mice (not shown) did not exhibit spike protein-specific CT values. nd denotes tissues in which spike protein-specific CT values were not detected. e. ΔCT values of spike-protein specific qPCR normalized to mouse GAPDH across multiple tissues and both timepoints. Box and whisker plots show min to max values. Individual values for each mouse are shown. Day 7 n = 3-4, Day 14 n = 4-6, Week 8 n = 1-5. f. Levels of viral spike protein RNA detected in the native mouse lung for all infected mice across all timepoints. ΔCT values of SARS-CoV-2 spike protein-specific qPCR were determined by normalizing the spike protein values against mouse GAPDH. Welch’s ANOVA test p-value = 0.0014, with an adjusted p-value = 0.005 between Hu and immunodeficient groups. Individual values for each mouse are shown. Hu/Hu n = 6, Hu n = 9, Immunodeficient n = 7. g. Log copies per microliter in RNA isolated from lung (left) and heart (right) tissue from nucleocapsid protein-specific qPCR. Copy numbers determined using a standard curve from provided nucleocapsid standards. Box and whisker plots show min to max values with adjusted p-values determined by one-way ANOVA. Individual values for each mouse are shown. Lung: Hu/Hu n = 4, Hu n = 5, Immunodeficient n = 3. One-way ANOVA p-value = 0.0142. Heart: Hu/Hu n = 4, Hu n = 5, Immunodeficient n = 3.

The new study reports that human immune cells can promote the dissemination of SARS-CoV-2 beyond the respiratory tract, with viral RNA persisting in multiple organs for weeks. Importantly, immune activation was also observed in tissues including the heart, intestine and brain.

The obvious question is:

How is the virus—or persistent viral material (Spike)—getting there?

One possibility deserves much attention: Could macrophages be acting as cellular Trojan horses?

This idea is not entirely new. In fact, a paper was written in 2021 discussing this very idea.

In conclusion, MN (monocytes) and MDM (monocyte-derived macrophages) are pivotal innate immune cells with a crucial role in defensive activities against various antimicrobial agents such as viruses. Besides this beneficial activity, they can exert unfavorable effects, extending viral infection within the body. However, their role has not yet been definitely established. Here, we showed that SARS-CoV-2 infects MN and MDM without production of the infectious virus but preserving infectivity. Therefore, these cells may act as spreaders for the virus in different body districts as a “Trojan horse”.

Macrophages and Monocytes: “Trojan Horses” in COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC8624282/

What the new paper shows is that macrophage dissemination is dependent on ACE2 expression!

We have observed persistent viral RNA and protein across multiple organs for up to 8 weeks along with inflammation and features of PASC. We have demonstrated that human immune cells promote the dissemination of virus to extrapulmonary organs and increase the level of pulmonary infection. Persistent viral RNA was associated with strong, long-lasting anti-viral immune responses in the heart while clearance of virus over time resolved inflammation in the brain. Our model uniquely recapitulates both prolonged viral persistence signatures and a human adaptive immune response in the context of physiologic hACE2 expression, providing new opportunities to explore PASC pathogenesis and evaluate therapeutic interventions targeting the virus-immune interface.

A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity
https://www.biorxiv.org/content/10.64898/2026.06.18.733232v1.full

And the presence of these SARS RNA-laden (Spike) macrophages are of the Smoldering variety.

To further investigate the transcriptional response to infection, we performed pseudobulk differential expression analysis and identified alveolar macrophages as the primary responder to infection, with 217 genes differentially expressed between infected and uninfected mice (Fig. 9c). Within alveolar macrophages, complement (Cfb), chemokines (CXCL2), and stress response genes (Mt1) were upregulated in response to infection, with significant transcriptional upregulation of NFkB1 (padj < 10-22) and PPARG (padj < 10-21), indicating a strong murine inflammatory macrophage response to infection

A novel model demonstrating that human immune cells promote multiorgan SARS-CoV-2 dissemination and human T cells limit anti-viral innate immunity
https://www.biorxiv.org/content/10.64898/2026.06.18.733232v1.full

So, there is the Spike-induced loop:

Spike enters/associates with monocytes → monocytes traffic to tissues → differentiate into macrophages → macrophages attempt to respond and repair → persistent Spike/inflammatory signaling prevents resolution → macrophages remain activated → chronic repair/remodeling continues → SMS.

How can we be confident in this assessment? Because the Spike abides – in macrophages.

Recent evidence suggests that immune cell persistence and reprogramming play a central role in these non-organ damaged related syndromes. Patterson et al. found that the SARS-CoV-2 S1 spike protein persisted in CD16+ monocytes up to 15 months post-infection in individuals with Long COVID, despite the absence of ongoing viral replication [7]. Complementary work by Simonis et al. revealed that mRNA vaccination induced durable epigenetic reprogramming in monocyte-derived macrophages, characterized by H3K27ac modifications and elevated IL-1β, TNF-α, and other inflammatory cytokines [8]. These findings demonstrate that spike protein exposure, whether through infection or vaccination, can lead to long-lasting macrophage activation [9].

The Central Role of Macrophages in Long COVID Pathophysiology
https://www.preprints.org/manuscript/202511.0998

The macrophage comes to heal—but it arrives altered. It contains Spike. It encounters a tissue that still carries the molecular signature of the original injury. And instead of completing the healing process and switching off, it remains activated. It continues to repair. It continues to remodel. It continues to recruit. It continues to signal. It overheals. And the healing response itself becomes pathological.

Smoldering Macrophage Syndrome.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Please have a blessed week.

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This schematic diagram illustrates the mechanisms of the potential of Panax notoginseng against COVID-19 infection.

As readers of this Substack know, I have, from the beginning, proposed that the Spike Protein induces a vascular disease which I have called Spike Protein Endothelial Disease (SPED). My continual search for therapeutics for this disease brings me to an especially interesting TCM herb:

Panax notoginseng.

Also known as Sanqi or Tianqi, P. notoginseng has been used for centuries in traditional Chinese medicine. Its major bioactive compounds include a collection of steroidal saponins known as notoginsenosides and ginsenosides.

The literature I have found suggests that this plant may do something particularly valuable: help protect the endothelium while supporting the body’s ability to repair damaged blood vessels. This could potentially reverse the damage done by SPED.

Protecting the endothelium/Treating SPED

One of the papers I found particularly compelling examined P. notoginseng in models of diabetes-associated vascular dysfunction.

Researchers found that both P. notoginseng extract and its total saponins protected endothelial function. They improved endothelium-dependent relaxation while reducing oxidative stress and endoplasmic-reticulum stress.

Importantly, the effect was associated with activation of the AMPK/eNOS pathway.

AMPK is an important regulator of cellular energy and vascular health, while eNOS produces nitric oxide—a critical molecule that allows blood vessels to relax and maintain normal vascular function.

In other words, P. notoginseng wasn’t simply acting as an antioxidant. It was influencing a pathway intimately involved in maintaining endothelial function.

The present study used multiple approaches to elucidate and compare the effects of PNS and PNE on endothelial dysfunction in diet-induced obese mice. Treatment with either PNS or PNE rescued the impaired endothelial function in a hyperglycemic condition and in diabetic obese mice, accompanied by enhancement of vascular AMPK/eNOS activities with inhibition of ER stress and oxidative stress. PNS (total saponin) was found to be more potent ex vivo and in vitro but PNE (ethanolic extract of P. notoginseng) was more effective in vivo.

Panax Notoginseng Protects against Diabetes-Associated Endothelial Dysfunction: Comparison between Ethanolic Extract and Total Saponin
https://pmc.ncbi.nlm.nih.gov/articles/PMC8437594/

Could it actually help rebuild damaged vessels, reversing SPED?

This is where the story gets even more interesting.

A 2013 study investigated P. notoginseng saponins in mice with atherosclerosis. The researchers found that treatment reduced atherosclerotic lesion size and the intima-to-media ratio while increasing endothelialization. But there was another remarkable finding. The treatment increased circulating and bone-marrow populations of endothelial progenitor cells. The authors concluded that the vascular benefits appeared to involve mobilization of progenitor cells, potentially through the SDF-1α/CXCR4 signaling system.

That suggests something more than simply protecting existing endothelial cells. It raises the possibility that P. notoginseng may help the body repair vascular injury.

Results: PNS (Panax notoginseng saponins) significantly reduced the lesion area and intima-to-media ratio compared to vehicle treatment. PNS also augmented endothelialization and reduced the smooth muscle cell (SMCs) content of the lesions. The number of c-kit and sca-1 double-positive progenitor cells and flk-1 and sca-1 double-positive progenitor cells were significantly increased in the BM and the peripheral blood of the PNS-treated groups. PNS treatment increased the plasma levels of SDF-1α and SCF as well as the BM levels of matrix metalloproteinase-9 (MMP-9). Moreover, the mRNA levels of SDF-1α and protein levels of CXCR4 were both increased in the BM of mice treated with PNS, while SDF-1α expression decreased.

Conclusion: PNS reduce the size of atherosclerotic plaques, and this effect appears to involve progenitor cell mobilization. SDF-1α-CXCR4 interactions and the possible modulatory role of PNS in this process may contribute to the increased progenitor cell mobilization.

Panax notoginseng saponins promote endothelial progenitor cell mobilization and attenuate atherosclerotic lesions in apolipoprotein E knockout mice
https://pubmed.ncbi.nlm.nih.gov/24080960/

And then there is COVID-19 infection itself

A 2023 mini-review specifically examined the potential of P. notoginseng against COVID-19.

The authors point to experimental evidence suggesting that P. notoginseng may help modulate the excessive inflammatory response associated with SARS-CoV-2 infection, including the cytokine cascade sometimes described as a cytokine storm. They also discuss its potential relevance to post-COVID symptoms.

Here, we have discussed the pharmacological potential of P. notoginseng; the material may control the cytokine storm. Accumulating evidence points to an anti-viral potential of P. notoginseng both in vitro and in vivo. In China, TCM formulae including Lianhuaqingwen, Jinhuaqinggan and Xuebijing are used to treat COVID-19 infection; natural products may be valuable in this context. P. notoginseng, a representative herbal medicine, and the various extracts thereof and mixed P. notoginseng compounds, inhibit the actions of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) by modulating signaling pathways including the MAPK, Mincle/NF-κB and JAK/STAT pathways. In addition, P. notoginseng can also relieve post-COVID-19 symptom.

The potential of Panax notoginseng against COVID-19 infection
https://www.sciencedirect.com/science/article/pii/S1226845323000313

This is important—but it needs to be interpreted carefully.

We do not yet have clinical evidence demonstrating that Panax notoginseng treats or prevents COVID-19 in humans. The COVID-specific evidence remains largely experimental and mechanistic. It is my hope that clinicians and those with labs reading this will conduct trials.

However, the point is that the hypothesis is fascinating because its potential benefits overlap with several biological processes implicated in COVID-19:

Inflammation.
Oxidative stress.
Endothelial dysfunction.
Vascular injury.
Impaired vascular repair.

And P. notoginseng appears to have biological activity across several of these pathways and may actually be a therapeutic that could reverse the damage caused by SPED.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Please have a blessed weekend.

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Association between HLA DRB1 alleles, the presence of case definition symptoms and T cell immune responses to SARS‐CoV‐2 following natural infection: (a) consistent association of DRB113:02 with the presence of case definition symptoms; (b) Association between the absence of HLA‐DRB115:02 and T‐cell responses against nucleoprotein peptide pool (HLA‐DRB115:02 −, n = 68, HLA‐DRB115:02 +, n = 5). Bars show mean with SD. P value calculated using a Mann–Whitney U test. PBMC for T cell assays were taken on average 121 (range 71–174) days following first presentation of case definition symptoms. HLA, human leukocyte antigen; PBMC, peripheral blood mononuclear cells

One person develops profound fatigue and post-exertional malaise. Another develops dysautonomia and exercise intolerance. Another experiences neurological symptoms, cognitive dysfunction, or sensory disturbances. Others develop gastrointestinal problems, endothelial dysfunction, cardiac symptoms, inflammatory or autoimmune manifestations—or combinations of all of these.

Why?

We have discussed multiple possible explanations: Different viral reservoirs, differences in acute disease severity, prior infections, vaccination history, autoimmunity, metabolic health, tissue vulnerability and environmental factors may all contribute.

Yet there is another possibility, there may be a mechanism that is lurking behind all the above explanations – and more:

Our HLA genotype may help determine what SARS-CoV-2 leaves behind—and how our immune system responds to it.

I believe HLA-DRB1 deserves investigation as a possible answer as to why the body’s response to SARS-CoV-2 and its Spike Protein seems to be individually tailored.

HLA-DRB1 is essentially part of the immune system’s “peptide presentation” machinery

HLA-DRB1 encodes the beta chain of an HLA class II molecule. Together with HLA-DRA, it forms the HLA-DR antigen-presenting complex.

Its job is extraordinarily important: HLA-DR molecules bind fragments of proteins and present those peptides to CD4+ T cells. But there is an important catch.

Different HLA-DRB1 alleles bind different peptides with different efficiencies.

In other words, two people can encounter the same virus but present different pieces of that virus (different pieces of Spike, for example) to their immune systems. Remember all the molecular mimicry of the Spike Protein which we have discussed extensively? That is paramount here. Especially in terms of an autoimmune response – those different pieces that are being presented.

Those different pieces can influence the subsequent immune response.

And HLA-DRB1 is extraordinarily polymorphic. Hundreds of alleles have been described, with differences concentrated in regions that determine peptide-binding specificity.

This gives us a potential mechanism for something that I have been seeking to understand in Long COVID: the same infection producing radically different long-term immune phenotypes.

Imagine two people encountering the same SARS-CoV-2 infection

Person A’s HLA-DRB1 molecules may efficiently present several immunodominant SARS-CoV-2 peptides. That could produce a rapid and coordinated CD4 T-cell response, effective B-cell help and efficient development of antiviral immunity.

Person B may present a different collection of viral peptides—or present some of them less efficiently. The consequences could be very different. Perhaps viral antigen is cleared less efficiently. Perhaps some reservoirs persist longer. Perhaps the immune response becomes disproportionately focused on particular viral proteins. Perhaps antibody responses develop differently. Or perhaps some of the peptides being presented resemble host proteins closely enough to contribute to autoreactive responses in genetically susceptible individuals.

My point is that HLA-DRB1 could help determine the starting conditions under which the immune system encounters persistent SARS-CoV-2 antigen.

Let’s Look at the Evidence

HLA variation has already been associated with differences in SARS-CoV-2 infection and disease.

For example, a study of more than 1,300 UK healthcare workers found that HLA-DRB113:02 was associated with a substantially increased risk of symptomatic COVID-19 among those who seroconverted. The same study found that HLA-DRB115:02 was associated with lower nucleocapsid-specific T-cell responses.

We investigated the association of HLAII alleles with case definition symptomatic COVID‐19, virus‐specific antibody and T‐cell immunity. A total of 1364 UK healthcare workers (HCWs) were recruited during the first UK SARS‐CoV‐2 wave and analysed longitudinally, encompassing regular PCR screening for infection, symptom reporting, imputation of HLAII genotype and analysis for antibody and T‐cell responses to nucleoprotein (N) and spike (S). Of 272 (20%) HCW who seroconverted, the presence of HLA‐DRB113:02 was associated with a 6·7‐fold increased risk of case definition symptomatic COVID‐19. In terms of immune responsiveness, HLA‐DRB115:02 was associated with lower nucleocapsid T‐cell responses.

HLA‐DR polymorphism in SARS‐CoV‐2 infection and susceptibility to symptomatic COVID‐19
https://pmc.ncbi.nlm.nih.gov/articles/PMC9111350/

Indeed, HLA alleles have also been proven to influence whether one develops Long COVID.

Demographic characteristics and relevant clinical history data were extracted from the medical records of 88 individuals diagnosed with LCS (LCS+) and 96 individuals without LCS (LCS−). Serum levels of anti-receptor binding domain IgG (anti-RBD IgG), anti-β2-glycoprotein I IgG (anti-β2GPI IgG), and C-reactive protein (CRP) were measured. Low-resolution genotyping was performed to identify HLA-DRB1* and HLA-DQB1* alleles. Logistic regression analysis was employed to examine the associations between HLA alleles and LCS status. Subsequently, mediation analysis was conducted to explore the potential mechanistic roles of anti-RBD IgG, CRP, and anti-β2GPI IgG in these observed relationships.

The LCS+ group exhibited a significantly higher frequency of the HLA-DRB101 allele and a lower frequency of the HLA-DRB111 than the LCS− cohort. Serum levels of both CRP and anti-β2GPI IgG were substantially higher in the LCS+ cohort, whereas anti-RBD IgG levels were significantly lower. After adjusting for key variables, HLA-DRB101 and HLA-DRB111 remained significantly associated with LCS. Mediation analysis suggested that these HLA associations might be partially mediated by CRP, anti-RBD IgG, and anti-β2GPI IgG levels.

Our findings indicate that the combination of HLA-DRB101 and HLA-DRB111 allele screening with serological profiling (anti-RBD IgG, CRP, and anti-β2GPI IgG) may contribute to refining predictive models of LCS susceptibility, though clinical utility requires validation in larger, independent cohorts.

HLA-DRB1* Alleles and Long COVID: A Mediation Analysis of Anti-RBD IgG, CRP, and Anti-β2GPI IgG
https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4581

It is my hope that further research into HLA-DRB1 alleles (and other HLA alleles) will help us to finally understand why SARS-CoV-2 and its Spike Protein affect all of us in such vastly different ways – including those of us who it seems to not affect at all.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Please have a blessed week.

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In endothelial cells cultured without TNF-α, incubation with 40 μg/mL HS extract (HS40) increased the production of the eNOS protein (A), eNOS’s mRNA expression (B), and the production of NO (C). The addition of l-NAME, an eNOS inhibitor, nearly eliminated NO production, and the effects of indomethacin, a cyclooxygenase inhibitor, were not significant (C). *p < 0.05 compared to the control. Values represent results obtained in triplicate from at least four experiments.

Hibiscus has been known to be an effective therapeutic since ancient times. Ancient Egyptian texts, for example, describe hibiscus preparations for cooling the body during fever. Traditional Persian medicine used it for cardiovascular health, while Ayurvedic and African herbal traditions valued it for inflammatory disorders, liver support, and hypertension. Long before molecular biology existed, cultures around the world recognized that this striking crimson flower seemed to promote resilience during illness.

Modern science is beginning to explain why.

Recent studies suggest hibiscus possesses an unusual combination of properties that make it particularly interesting in the context of SARS-CoV-2 and its Spike Protein: it appears capable of reducing viral replication, dampening harmful inflammation, and protecting the vascular endothelium simultaneously.

Let’s look at each of these aspects individually.

Slowing Viral Replication

One of the more intriguing discoveries is that extracts from Hibiscus demonstrate direct antiviral activity against SARS-CoV-2 in laboratory studies.

Researchers found that hibiscus extracts reduced SARS-CoV-2 replication within infected cells, in part by inhibiting the viral main protease (3CLpro), an enzyme essential for viral replication. The antiviral activity was attributed largely to the anthocyanin cyanidin-3-sophoroside-5-glucoside, one of the major bioactive compounds found in Hibiscus.

Our research aimed to perform sequential in silico investigations including molecular docking, ligand–protein interaction, physiochemical, ADMET and drug-likeness properties prediction to discover potential phytochemical inhibitors against 3CLproenzyme to terminate the proliferation of SARS-CoV-2.We identified cyanidin-3-sophoroside-5-glucosideisolated from Hibiscus rosa-sinensis flower [50] as a potential drug candidate that targets the His-41 residue of the catalytic dyad and binds strongly to the active site of 3CLpro with a binding affinity of − 10.9 kcal/mol. Following the majority of parameters of physiochemical, ADMET and drug-likeness properties analysis predicts the stability of cyanidin-3-sophoroside-5-glucoside in the biological system. From this study, we conclude that the identified novel phytochemicalcyanidin-3-sophoroside-5-glucosidehas potential inhibitory action against SARS-CoV-2.

An in silico study on phytochemicals from Hibiscus rosa-sinensis as potential inhibitors of SARS-CoV-2 3CLpro
https://link.springer.com/article/10.1007/s42452-025-07595-w

Ameliorating Inflammation

Next, let’s look at the evidence demonstrating how Hibiscus may be helpful in ameliorating inflammation (particularly lung-related) caused by the virus and its Spike Protein. Note the pathways that Hibiscus modulates.

The studies by Alsharif et al. (2021) and Zhang et al. (2015) demonstrate the therapeutic potential of protocatechuic acid (PCA - a natural phenolic antioxidant found in the dried flowers and calyces of Hibiscus) in lipopolysaccharide (LPS)‐induced acute lung injury (ALI). Alsharif et al. (2021) showed that pre‐administration of PCA significantly attenuates lung damage associated with the septic response, through its antioxidant, anti‐inflammatory, and anti‐apoptotic properties. In addition, Zhang et al. (2015) showed that the administration of PCA reduced pulmonary histopathological changes, the concentration of proteins in the bronchoalveolar fluid, and the overproduction of proinflammatory cytokines TNF‐α and IL‐1β. In addition, PCA at a dose of 30 mg/kg inhibited the activation of the p38MAPK and NF‐κB signaling pathways, central mechanisms in the modulation of inflammation. These results reinforce the role of PCA as a protective agent in experimental models of ALI, indicating its potential use in the treatment of inflammatory lung diseases.

Applicability of Hibiscus sabdariffa L. Extract With Anti‐Inflammatory Potential in Human Health: A Review
https://pmc.ncbi.nlm.nih.gov/articles/PMC12455510/

Protecting the Endothelium

One more therapeutic aspect of Hibiscus that I would like to discuss today is beneficial regardless of the presence or absence of the SARS-CoV-2 virus and its Spike Protein. Hibiscus is also very adept at protecting the endothelium!

This study provides a research framework for assessing the effects of HS polyphenols on conditions associated with hypertension and the multifaceted metabolic syndrome 20, combining human and animal studies with ex vivo and in vitro experiments. There are several mechanisms involved. Diuresis, or inhibition of ACE activity are probably not important mechanisms of HS’ hypotensive effect. Rather, we interpret our findings as proof of the beneficial effects of polyphenols on free radicals and immune modulation. It is likely that these actions could improve cardiovascular health. Our ex vivo data also contribute to this conclusion and add a beneficial endothelial response, probably vasodilation, to a better understanding of the possible mechanisms of action. Taken together, our results suggest that a multifaceted and likely synergistic mechanism accounts for the hypotensive action of polyphenol-rich HS, which acts through improved endothelium-dependent response.

Hibiscus sabdariffa extract lowers blood pressure and improves endothelial function
https://onlinelibrary.wiley.com/doi/10.1002/mnfr.201300774

One of the recurring themes in my own research is that therapies capable of addressing multiple components of disease simultaneously may offer the greatest benefit.

Hibiscus appears to do exactly that.

It may:

• Reduce SARS-CoV-2 replication.

• Suppress chronic inflammatory signaling.

• Lower oxidative stress.

• Improve endothelial function.

• Support vascular health independently of any antiviral effects.

• Each of these actions alone would be valuable.

Together, they suggest a therapeutic profile remarkably well aligned with many of the biological abnormalities observed in both acute COVID-19 and persistent post-COVID illness.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Please have a blessed weekend.

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(A) Representative images showing the conduction tissue marker contactin 2 (red) and the distribution of Iba1+ macrophages (green) in the region. (B) Representative images showing Iba1+ and CD163+ macrophages in the conduction region in mock- or SARS-CoV-2–infected hearts at 4 and 28 dpi. (C and D) Density of Iba1+ cells and CD163+ cells in CCS region of the mock- or SARS-CoV-2–infected hearts at 4 and 28 dpi. (E and F) Gene expression of cytokines and IFN-stimulated genes in lung (E) and heart (F) at 4 dpi, evaluated with qPCR. Unpaired 2-tailed t test was used to test for significance in normally distributed lung data in E. Mann-Whitney U test was used as the nonparametric significance test in heart data in F. (G and H) SARS-CoV-2 nucleocapsid protein was detected in lung, but not in the heart, by Western blot (G) or by immunofluorescence (H) at 4 dpi. (I) Viral spike protein mRNA was detected in lung, but not in the heart, by qPCR at 4 dpi. Unpaired 2-tailed t test.

I referred to the Spike Protein shortly after the beginning of the Pandemic as being a “Swiss Army Knife of Death.” The graphic I created illustrating this is now ubiquitous with many claiming to have created it. I care not. The point is that the information is out there.

Today I would like to discuss another “tool” in this lethal multi-purpose weapon. This tool is the ability of the Spike Protein to remove (alter to a harmful state) cardiac resident macrophages.

To understand this, let’s look at what cardiac resident macrophages do. They prevent sudden cardiac death during heart stress by maintaining cardiac impulse conduction, preventing lethal arrythmias.

Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Because right ventricular (RV) dysfunction increases the risk for sudden cardiac death, we examined responses to RV stress in mice. Among immune cells accumulated in the RV after pressure overload-induced by pulmonary artery banding, interfering with macrophages caused sudden death from severe arrhythmias. We show that cardiac macrophages crucially maintain cardiac impulse conduction by facilitating myocardial intercellular communication through gap junctions.

Cardiac macrophages prevent sudden death during heart stress
https://www.nature.com/articles/s41467-021-22178-0

In the context of the Spike Protein, we discover something very interesting. Patients with severe COVID have reduced numbers of these protective macrophages vs inflammatory macrophages.

Interestingly, patients with severe COVID disease have increased numbers of inflammatory monocyte-derived macrophages (v.v. resident macrophages); a macrophage subset that has been shown to express gene programs associated with tissue repair and fibrosis [15].

“Role of Cardiac Inflammation in the Pathology of COVID-19; relationship to the current definition of myocarditis”
https://pmc.ncbi.nlm.nih.gov/articles/PMC9061642/

Also, observe the extremely dramatic loss in density of these protective macrophages following COVID infection.

Following SARS-CoV-2 infection at 4 dpi, significant macrophage infiltration was observed throughout the heart, and the density of Iba1+ macrophages increased by 78% in the AV node/His bundle region of COVID-19 animals compared with mock-infected controls (Figure 3C). Despite the increase in macrophage infiltration, the density of CD163+ macrophages decreased by 74% in the AV node/His bundle region.

Innate immune activation and mitochondrial ROS induce acute and persistent cardiac conduction system dysfunction after COVID-19
https://insight.jci.org/articles/view/193164

Yet, what is most important here is that COVID infection (the complete virus) need not be present to induce this potentially catastrophic situation. The Spike Protein alone can induce it.

Cardiac arrhythmias are a common complication in severe and fatal cases of COVID-19, with increased arrhythmia incidence correlated with severity of viral infection2,3. These patients also have heightened activation of resident macrophages and elevated expression of inflammatory cytokines and show evidence of vascular damage and cardiac remodeling. Identifying the pathophysiologic origins of cardiac arrhythmias in severe and fatal COVID-19 has inspired much debate. A number of studies, using in vitro heart tissue and human induced pluripotent stem cells, have suggested that cardiac damage may result from direct infection of myocytes by SARS-CoV229,30. Yet, others have proposed cardiac arrhythmias as a consequence of the systemic cytokine storm following viral infection9,10,11. We have previously provided strong evidence, using human cardiac tissue from fatal COVID-19 cases, that acute insult from viral spike protein triggers inflammation-induced vascular leak and consequent proarrhythmic disruption of NaV1.5-rich ID nanodomains7. Briefly, histologic and molecular studies in cardiac tissue from 11 fatal COVID-19 cases demonstrated presence of perivascular viral spike protein, elevated expression of pro-inflammatory cytokines, considerable microvascular damage including perivascular edema, and remodeling of key ID components essential for proper impulse propagation. SARS-CoV2 RNA was not detected with an ultrasensitive in situ hybridization method, consistent with other findings that note the lack of viral RNA despite clearly evident cardiac abnormalities in fatal COVID-197,9,12,15. These findings were consistent with results from our previously defined arrhythmia mechanism, whereby inflammation-induced vascular leak, and consequent edema, disrupts ID nanodomains and slows conduction, thereby generating a proarrhythmic substrate16.

SARS-CoV-2 spike protein-induced inflammation underlies proarrhythmia in COVID-19
https://www.nature.com/articles/s41598-025-12807-9

If persistent spike antigen maintains a chronic, low-grade inflammatory state—as proposed in the Smoldering Macrophage Syndrome hypothesis—the continual replacement of resident macrophages by inflammatory monocyte-derived macrophages could impair the specialized support these cells provide to the cardiac conduction system. This possibility has not yet been directly tested but deserves investigation.

At the postsynaptic level, we previously showed that infiltrating monocyte-derived macrophages increased and resident macrophages decreased in the cardiac conduction system during the acute phase of SARS-CoV-2 infection.20 The early loss of resident macrophages was prevented by mTEMPO or Ruxo, without significant effects on the infiltration of monocyte-derived macrophages.20 Thus, the loss of important supporting functions of resident macrophages50 in the conduction system could contribute to altered neuron-pacemaker interactions. Activation of the innate immune system has been shown to induce chronic inflammation or neuropathy via neuroimmune cross talk,51 and there is increasing evidence that SARS-CoV-2 infection is associated with neuroinflammation and disorders of the cranial and peripheral nervous system,34,52 which could contribute to ANS dysfunction in patients with long COVID.

Dynamic changes in cardiac autonomic function persist in the postacute phase after SARS-CoV-2 infection in a hamster model of COVID-19
https://www.sciencedirect.com/science/article/pii/S2666501826002515

The evidence now paints a compelling picture. Cardiac resident macrophages are essential components of the heart’s electrical conduction system, helping maintain normal impulse propagation and protecting against lethal arrhythmias. Independent studies have shown that SARS-CoV-2 infection depletes these specialized macrophages while replacing them with inflammatory monocyte-derived populations, and that the Spike Protein alone can provoke inflammatory remodeling of cardiac tissue even in the absence of detectable viral RNA. If persistent Spike antigen continues to sustain low-grade innate immune activation, as proposed in the Smoldering Macrophage Syndrome hypothesis, then the chronic loss or dysfunction of these protective resident macrophages could represent one previously overlooked mechanism linking persistent spike exposure to long-term cardiac electrical instability and sudden cardiac death.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Also, a great thank you to the generous donor who contributed over the weekend. Please have a blessed week.

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When researching the literature for a natural therapeutic which may be useful in treating my proposed Smoldering Macrophage Syndrome, I found one that stands out. It seems almost custom-tailored to treat the disease. It is Andrographolide (Andro) and, it is known colloquially as the “King of Bitters” for the highly concentrated bitter taste of the Andrographis paniculata plant. It is also a staple of Traditional Chinese Medicine.

Andrographolide is a diterpene lactone compound extracted from Andrographis paniculata (Burm. F) Nees. Andrographis paniculata is also known as lanhelian, yijianxi, zhanshecao, kucao, kudancao, etc. Since this product originates in India, it is also known as Indian grass. This product is dry ground part of Jupiteraceae plant Andrographis paniculata (conus) may originate in South Asia. It is commonly cultivated in China such as in Fujian, Guangdong, Hainan, Guangxi, and Yunnan and also in Australia and was also introduced in Jiangsu and Shaanxi.

Andrographis paniculata is commonly used in traditional Chinese medicine. Its ability of relieving “snake venom, and internal injuries cough” was recorded in “Lingnan herbal medicine records.” “Quanzhou Materia Medica” described it as “heat-clearing and detoxifying, anti-inflammatory, detumescence and inhibition throat inflammation, dysentery and high fever.”

Andrographolide
https://pmc.ncbi.nlm.nih.gov/articles/PMC7122281/

Why it caught my attention is that it shows properties of being theoretically able to bind Spike Protein, prevent Foam Cell formation and quell cytokine release from activated macrophages. All three of these actions would ameliorate Smoldering Macrophage Syndrome.

First, let’s look at how Andro can potentially bind Spike, preventing it from entering cells.

In this study, we used docking and molecular dynamics simulations to understand the binding effect of andrographolide on the SARS-CoV-2 spike protein. During docking, a strong binding affinity was observed between the ligand and the target receptor protein. MD results demonstrated higher conformational fluctuations in the ligand-free protein compared to the bound form. Several residues in the active sites make conformational rearrangements for the S protein to interact with the ligand. While RBD experiences conformational transition to gain more stability upon binding with the ligand. This binding is strengthened via several non-covalent interactions that make the complex structure more stable with higher binding affinity. Overall findings of the study may shed some valuable insights concerning the development of potential therapeutics in the strategies for COVID-19 prevention.

Investigating the binding affinity of andrographolide against human SARS-CoV-2 spike receptor-binding domain through docking and molecular dynamics simulations
https://pubmed.ncbi.nlm.nih.gov/36764825/

Next, Andro has demonstrated abilities to prevent the formation of foam cells, which we have previously discussed as an action the Spike Protein is able to induce.

In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.

Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages
https://pubmed.ncbi.nlm.nih.gov/29298513/

The remaining property of Andro I would like to discuss today is its ability to reduce the expression of cytokines in macrophages. Specifically, the expression of cytokines the Spike is particularly fond of increasing.

Macrophages have remarkable heterogeneity and plasticity that allows them to efficiently respond to exogenous and endogenous signals by changing their functional phenotype11, 14. In this study, thioglycollate-elicited mouse peritoneal macrophage (F4/80+ population)26 have been used to investigate the immunomodulatory activities of andrographolide on the innate immune response in vitro. Our results indicated that andrographolide showed potent immunoregulatory properties in murine macrophages. Andrographolide reduced expression of inflammatory cytokines (TNF-α, IL-12, IL-1β, IL-18, and IL-6) in LPS activated macrophages, which is consistent with a previous report that andrographolide decreased TNF-α and IL-12 mRNA expression and cytokine production in murine peritoneal macrophages, although they did not detect IL-1β, IL-18, and IL-627.

Immunomodulatory activity of andrographolide on macrophage activation and specific antibody response
https://pmc.ncbi.nlm.nih.gov/articles/PMC4002847/

Now it is clear why andrographolide captured my attention: Because it appears to address both sides of the SMS equation.

If Smoldering Macrophage Syndrome is driven by persistent viral stimulation together with macrophages that remain trapped in a chronic inflammatory state, then the ideal therapeutic would do more than simply suppress inflammation. It would reduce the viral stimulus while helping restore normal macrophage biology.

Andrographolide appears to move in exactly those directions.

We examined studies which suggest antiviral activity against SARS-CoV-2. Other studies demonstrated that it limits pathological cytokine production by activated macrophages. Still others show that it prevents macrophages from transforming into foam cells by restoring cholesterol homeostasis.

Taken together, these actions make andrographolide one of the most intriguing natural compounds I have encountered in the context of my Smoldering Macrophage Syndrome hypothesis.

Thank you, as always, for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Also, a great thank you to the three new paid subscribers who have joined us since Monday. Please have a blessed weekend.

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Most physicians are familiar with Macrophage Activation Syndrome (MAS)—a rare but devastating condition in which macrophages become explosively activated. Patients develop overwhelming inflammation, high fevers, liver dysfunction, dangerously elevated ferritin, and in severe cases, multiple organ failure. It is an immune system in hyperoverdrive.

Fortunately, very few people with COVID-19 or Long COVID develop MAS.

But what if the opposite problem is occurring?

What if macrophages aren’t exploding...

What if they’re simply refusing to stop?

A Different Kind of Macrophage Disease

Instead of producing an acute cytokine storm over days, imagine macrophages remaining partially activated for months—or even years.

Rather than causing dramatic organ failure, they quietly simmer, producing inflammatory cytokines, recruiting additional monocytes, stimulating fibrosis, remodeling blood vessels, and gradually impairing normal tissue repair.

I would like to propose this chronic state as a hypothesis:

Smoldering Macrophage Syndrome (SMS).

Unlike MAS, the fire never becomes an inferno.

Instead...

It simply never goes out.

What brought me to this hypothesis? The Spike Protein persists for a VERY LONG TIME in macrophages. And, as I have stated FROM THE BEGINNING. SPIKE IS SPIKE. The source matters not. It is evident from both infection – and vaccination.

We next assessed if Mac (Macrophages) were a viral source by quantifying spike protein in BALF CD45+CD64+ Mac using intracellular flow cytometry (Fig. 2b). Spike+ Mac was detected in 12 of 15 WCM and 8 of 10 OCM (Fig. 2c). Spike+ Mac frequency was 41% in WTMhi and OMhi, 25% in WTMlo and OMlo and 8.6% in WTMneg and OMneg (Fig. 2c). Spike+ Mac frequency correlated positively with viral RNA in total BALF cells and negatively with BALF Mac survival in culture (Fig. 2c).

To further assess SARS-CoV-2 replication in Mac, we examined double-stranded RNA and nonstructural protein 3 (NSP3) protein expression in BALF Mac over an 18-h culture period (Fig. 2d–f). At 8 h of culture, viral dsRNA and NSP3 proteins were increased in BALF Mac in all 8 WTMhi or OMhi, 5 of 9 WTMlo or OMlo and 3 of 8 WTMneg or OMneg (Fig. 2f and Extended Data Fig. 3a). Spike protein further increased over time in all WTMhi/OMhi and WTMlo/OMlo, but not in 4 of 8 OMneg macaques, suggesting SARS-CoV-2 had the ability to replicate in Mac. We also noticed an increased number of BALF Mac syncytia during the culture period, likely mediated by spike (Extended Data Fig. 3b), and filiform extensions in BALF Mac at 8 h of culture (Extended Data Fig. 3b), which facilitated connections between Macs (Fig. 2g). Confocal images showed NSP3 protein within some of these protrusions (Fig. 2d and Extended Data Fig. 3b), suggesting viral replication in BALF Mac through cell-to-cell propagation.

SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
https://www.nature.com/articles/s41590-023-01661-4

Perhaps most damning:

Tissue-Level Molecular and Histopathologic Findings: Serial skin biopsies at 1,160, 1,249, and 1,364 days post-vaccination, all from truncal skin within areas of clinically active Grover’s disease, were nucleocapsid negative and demonstrated persistent spike protein deposition in endothelial cells and macrophages by automated immunohistochemistry with histopathologic correlation. Spike protein was also found in nerve fibers at 1,364 days. The 1,364-day skin biopsy contained multiple plasmid DNA elements, including spike gene sequences (S1-S3), ori1/ori2, and the SV40 enhancer, confirming durable retention of vaccine-derived DNA in somatic tissue by PCR amplification with agarose gel electrophoresis and Sanger sequencing.

Persistence of Vaccine mRNA, Plasmid DNA, Spike Protein, and Genomic Dysregulation Over 3.5 Years Post-COVID-19 mRNA Vaccination
https://esmed.org/MRA/mra/article/view/7631

However, in all of this I find hope and healing because macrophages are remarkably adaptable.

Unlike permanently damaged tissue, macrophages continuously change their phenotype in response to their environment. If the chronic stimulus (Spike) is removed—or if therapies can restore normal immune regulation—it may be possible to shift them away from a persistent inflammatory state and back toward one that supports tissue repair and resolution.

Perhaps Long COVID is not simply a disease of excessive inflammation.

Perhaps, in many patients, it is a disease of unresolved inflammation.

And if that is true...

Helping macrophages remember how to stop may become just as important as helping them fight.

Thank you for keeping me going. I appreciate all of your support and am always grateful to everyone in our community. Also, a great thank you to the generous donor who contributed over the weekend and to the two new paid subscribers who have joined us since Friday. Please have a blessed week.

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When I discuss a pathological aspect of COVID and/or the Spike Protein, I feel compelled to search for answers. This week was no exception. After studying the literature, I found a natural supplement that actually addresses the issue of downregulated FcγRIIB: Resveratrol. Again, I find it fascinating how so many players in the field of natural COVID/Spike therapeutics play multiple roles. In this case, Resveratrol not only increases the expression of FcγRIIB, it also has been shown to be helpful in treating the very same autoimmune diseases most likely to occur post COVID/Spike Protein exposure.

Mice lacking FcγRIIB spontaneously develop lupus-like autoimmune disease with high autoantibody production and immune-complex injury. It is a reminder that the immune system depends just as much on inhibition as it does on activation. This finding was part of the foundation for Monday’s hypothesis that Spike molecular mimicry with FcγRIIB may be inducing a similar lack of FcγRIIB in humans.

FcγRIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell (PC) differentiation. Here, we analyzed the effect of B cell–intrinsic FcγRIIB expression on B cell activation and PC differentiation. Loss of FcγRIIB on B cells in Fcgr2b–conditional KO (Fcgr2b-cKO) mice led to a spontaneous increase in autoantibody titers.

FcγRIIB regulates autoantibody responses by limiting marginal zone B cell activation
https://www.jci.org/articles/view/157250

As I stated earlier, this is where Resveratrol may have added therapeutic value in treating/preventing autoimmune complications from COVID/Spike Protein. Resveratrol may compensate for FcγRIIB’s diminished expression in the context of COVID/Spike Protein by increasing its expression.

Resveratrol, an anti-inflammatory agent, can inhibit pro-inflammatory mediators by activating Sirt1, which is a class III histone deacetylase. However, whether resveratrol can regulate inhibitory or anti-inflammatory molecules has been less studied. FcγRIIB, a receptor for IgG, is an essential inhibitory receptor of B cells for blocking B-cell receptor-mediated activation and for directly inducing apoptosis of B cells. Because mice deficient in either Sirt1 or FcγRIIB develop lupus-like diseases, we investigated whether resveratrol can alleviate lupus through FcγRIIB. We found that resveratrol enhanced the expression of FcγRIIB in B cells, resulting in a marked depletion of plasma cells in the spleen and notably in the bone marrow, thereby decreasing serum autoantibody titers in MRL/lpr mice. The upregulation of FcγRIIB by resveratrol involved an increase of Sirt1 protein and deacetylation of p65 NF-κB (K310).

Upregulation of FcγRIIB by resveratrol via NF-κB activation reduces B-cell numbers and ameliorates lupus
https://pmc.ncbi.nlm.nih.gov/articles/PMC5628277/

If we look at the autoimmune diseases most likely to occur post COVID/Spike Protein exposure, Resveratrol has shown its worth in treating those diseases.

SLE (Lupus)

With regard to lupus cardiovascular disease, in vivo studies revealed that RSV (Resveratrol) has a therapeutic effect on atherosclerotic cardiovascular disease in SLE due to its antioxidant properties (101,106). These results were confirmed in vivo in a double-knockout ApoE−/− FAS−/− SLE mouse model (106). The authors found that mice in the RSV-treated group had fewer atherosclerotic plaques than those in the untreated group (not statistically significant), and that 43% of the RSV-treated animals had no plaques (106). In a different study, the authors evaluated the progression of aortic atherosclerosis in mice with SLE associated atherosclerosis after 10 weeks of oral treatment with RSV 0.3–0.4 mg/day in the treatment group (101). RSV was found to counteract the effect of SLE on atherosclerosis by preventing lipid excess by increasing cholesterol efflux (101). These findings suggest that RSV therapy may provide a novel approach to reduce the atherosclerotic cardiovascular effects of SLE.

In addition, a recent study also found that in lupus mice treated with water containing 0.01% RSV, RSV increased the level of SIRT1 in the hippocampus and decreased the level of vascular endothelial growth factor and C-X3-C motif chemokine ligand 1 (CX3CL1) by activating adenosine A2A receptors, but it was not statistically significant. It also showed a tendency to improve motor coordination in arteriosclerosis-prone lupus mice (107). This finding indicated that RSV may be a potential therapeutic candidate for the regulation of cognitive dysfunction in neuropsychiatric lupus, especially in motor disorders.

Potential of resveratrol in the treatment of systemic lupus erythematosus (Review)
https://www.spandidos-publications.com/mmr/30/4/182

RA (Rheumatoid Arthritis)

Resveratrol, a natural phytohormone, has attracted much attention in recent years owing to its therapeutic effects on RA. It was found that resveratrol can inhibit mitogen-activated protein kinase (MAPK), nuclear factor κB (NF-κB), and other cellular signaling pathways, thereby inhibiting the production and release of interleukins, proinflammatory cytokines, and matrix metalloenzymes. In addition, resveratrol can induce the apoptosis of MH7A, FLS, and inflammatory cells in RA, regulate macrophage differentiation and function, and protect the normal redox kinetics of mitochondria. Furthermore, resveratrol can effectively relieve synovial inflammation, proliferation, and cartilage destruction in RA. In particular, resveratrol has been shown to reduce RA-related complications, such as periodontitis, AF, and interstitial pneumonia.

The role of resveratrol on rheumatoid arthritis: From bench to bedside
https://pmc.ncbi.nlm.nih.gov/articles/PMC9465647/

Diabetes

Lee et al. (2011) conducted an investigation to assess the potential of resveratrol in preventing and treating Type 1 Diabetes (T1DM). In their study, resveratrol was administered both orally (at a dose of 250 mg/kg) and via subcutaneous injection (at a dose of 25 mg/kg) to non-obese diabetic mice. The results were striking, as they revealed not only prevention of T1DM but also the reversal of more advanced stages of insulitis within the islets of Langerhans.

Unveiling resveratrol’s potential: Navigating the landscape of autoimmune diseases
https://www.sciencedirect.com/science/article/pii/S2097382924000167

Resveratrol is eagerly raising its hand to answer the call for COVID/Spike Protein therapeutics. It is my hope that clinicians and researchers with labs will embark on studies using Resveratrol in treating/preventing the autoimmune conditions most commonly seen after COVID/Spike Protein exposure. Of course, please remember that this is a work of medical research and not medical advice. Always consult with your primary care provider before using any supplement or medication.

Thank you for keeping me going. I appreciate all of your support and am always grateful to everyone in our community. Please have a blessed weekend.

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A review was just published on July 10^th which discusses the incidence and types of autoimmune disease post COVID infection. What I found interesting (see above table) is that connective tissue disorders were at the top of the list.

Taken together, the evidence supports a clinically meaningful but provisional conclusion: SARS-CoV-2 infection is associated with an increased risk of incident autoimmune disease, the association is strongest for connective tissue, vasculitic, and antibody-mediated disorders, and it is modulated by infection severity, time since infection, and possibly vaccination. The implications for practice are that clinicians should remain alert to new autoimmune presentations in the post-acute period after COVID-19, particularly in patients who experienced severe acute illness, while recognising that the absolute risk for any individual condition remains low. The implications for research are that future studies should prioritise active outcome ascertainment with serological and clinical confirmation, incorporate infection comparators to control for surveillance effects, extend follow-up to distinguish transient from durable risk, and stratify by variant and vaccination status. Only with such designs can the field move from demonstrating association toward establishing causation and quantifying attributable risk with confidence. In parallel, the identification of serological or transcriptomic biomarkers capable of flagging individuals at elevated risk would allow post-infection surveillance to be targeted rather than applied indiscriminately, improving both its diagnostic yield and its cost-effectiveness.

Autoimmune Manifestations Following COVID-19 Infection: A Systematic Review
https://www.cureus.com/articles/508282-autoimmune-manifestations-following-covid-19-infection-a-systematic-review#!/

Dysfunction of a receptor called FcγRIIB is directly tied to the development of connective tissue autoimmune disorders. Including Lupus.

Abnormalities in B cell function and in the clearance and inflammatory response to immune complexes are characteristic features of SLE. As FcγRIIB is a key regulator of B cells, and low affinity FcγRs are central to the response to immune complexes, FcγRIIB might be expected to be involved in the pathogenesis of SLE and perhaps other autoimmune diseases.

The most direct evidence for the role of FcγRIIB in SLE comes from studies involving genetically modified mice1. FcγRIIB deficiency renders normally resistant strains of mice susceptible to several antibody- or immune complex-dependent models of autoimmunity, including immune complex-mediated alevolitis51 and glomerular basement membrane-specific antibody-mediated nephritis67,105.

FcγRIIB-deficient mice backcrossed to a C57BL/6 background spontaneously develop hypergamma-globulinaemia, autoantibodies and an immune complex-mediated disease resembling SLE106; this does not occur on mice backcrossed to a BAlB/c background, indicating the importance of strain-specific epistatic effects on autoimmune susceptibility. The restoration of FcγRIIB expression levels on bone marrow cells of (NZB × NZW) F1 mice (a mouse model of spontaneous SLE) using an FcγRIIB-expressing retrovirus can prevent autoimmunity107, and modest transgenic overexpression of FcγRIIB on B cells markedly reduces the development of SLE in MRL-lpr mice42. Thus, studies in genetically modified mice implicate FcγRIIB in the pathogenesis of auto immunity and the maintenance of B cell tolerance. Some uncertainty remains, however, owing to the possibility that neighbouring genes might be influencing the phenotype of FcγRIIB-deficient mice (see BOX 1).

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications
https://pmc.ncbi.nlm.nih.gov/articles/PMC4148599/

And Rheumatoid Arthritis.

Collagen-induced arthritis (CIA) is a B cell-dependent mouse model of inflammatory arthritis that shares some features with rheumatoid arthritis. FcγRIIB deficiency increases both collagen-specific IgG titres and disease severity in CIA52. Consistent with this, FcγRIIB B cell transgenic mice show a reduction in disease severity and in collagen-specific IgG titres; however, this effect was not observed in FcγRIIB macrophage transgenic mice42. In addition to influencing CIA through it effects on antibody production, FcγRIIB may also limit cartilage destruction by inhibiting the production of matrix metalloproteinases115.

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications
https://pmc.ncbi.nlm.nih.gov/articles/PMC4148599/

Why is this so important? FcγRIIB is one of the immune system’s most important inhibitory receptors. Unlike activating Fc gamma receptors, FcγRIIB functions as a brake. When immune complexes bind to both the B-cell receptor and FcγRIIB, intracellular signaling through its ITIM motif recruits phosphatases such as SHIP1, suppressing further B-cell activation and antibody production.

In simple terms, FcγRIIB helps tell the immune system:

“You’ve done enough. Stop.”

Without that inhibitory signal, B cells remain more easily activated, plasma cells continue producing antibodies, and immune tolerance becomes increasingly difficult to maintain.

FcγRIIB is the only inhibitory Fc receptor. It controls many aspects of immune and inflammatory responses, and variation in the gene encoding this protein has long been associated with susceptibility to autoimmune disease, particularly systemic lupus erythematosus (SLE). FcγRIIB is also involved in the complex regulation of defence against infection.

FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications
https://pmc.ncbi.nlm.nih.gov/articles/PMC4148599/

To bring this all together, one particularly intriguing finding comes from a computational structural analysis published in Viruses. Using AlphaFold2-derived structural comparisons, the investigators identified a Spike-derived epitope (TGIAV) with striking structural similarity to an exposed region of FcγRIIB. The similarity (RMSD 0.17 Å) led the authors to nominate FcγRIIB as a potential target of Spike-induced molecular mimicry.

Human AF-3D-mimics for SARS-CoV-2 Spike.

• Motif- TGIAV

• Protein - Low affinity immunoglobulin gamma Fc region receptor II-b

• RMSD (Å) - 0.17

• Z-Score - −1.63

• EpiScore - 29.41

• AlphaFold2 ID - AF-P31995-F1-model_v1_A

Potential Autoimmunity Resulting from Molecular Mimicry between SARS-CoV-2 Spike and Human Proteins
https://www.mdpi.com/1999-4915/14/7/1415

This hypothesis needs to be thoroughly tested, yet it provides a biologically plausible mechanism that could contribute to the increased incidence of connective tissue and other antibody-mediated autoimmune diseases reported after SARS-CoV-2 infection/Spike Protein exposure. Determining whether anti-Spike antibodies actually bind and impair FcγRIIB should now be an important experimental priority.

As I always state, thank you for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Great thanks to the two new Paid Subscribers who have joined since Friday. Please have a blessed week.

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If my hypothesis in Monday’s post is correct that persistent Spike Protein contributes to an Obliterative Foam-Cell Arteriopathy (OFCA) within the microvasculature, then an obvious question follows:

Can we slow or even prevent foam-cell formation?

This is an important question as foam cells are involved in COVID pathology independently of my proposed mechanism.

COVID-19 and long COVID are characterized by a dysregulated immune response. However, the role of macrophages during viral infection is poorly defined. Here we demonstrate that SARS-CoV-2 infection results in increased macrophage numbers and extensive formation of enlarged lipid-laden macrophages or foam cells using humanized mice, rhesus macaques and post-mortem human lung tissue.

SARS-CoV-2 infection induces pro-fibrotic and pro-thrombotic foam cell formation
https://www.nature.com/articles/s41564-025-02090-9

While no nutraceutical has been proven to reverse this proposed process in Long COVID, three natural compounds repeatedly emerge in the scientific literature for their ability to target the very biology that creates foam cells. And they should sound very familiar to us: berberine, resveratrol and curcumin.

As an ensemble, they attack the foam-cell problem from complementary directions.

Let’s start with berberine.

Berberine reduces the amount of oxidized LDL entering macrophages while simultaneously increasing cholesterol efflux through the LXRα–ABCA1 pathway. In simple terms, it helps macrophages remove cholesterol rather than becoming bloated with it. Multiple studies have demonstrated that berberine suppresses foam-cell formation in experimental models by enhancing reverse cholesterol transport and reducing lipid accumulation.

Berberine, a botanical alkaloid purified from Cortidis rhizoma, has effects in cardiovascular diseases, yet the mechanism is not fully understood. Foam cells play a critical role in the progression of atherosclerosis. This study aimed to investigate the effect of berberine on the formation of foam cells by macrophages and the underlying mechanism. Treatment with berberine markedly suppressed oxidized low-density lipoprotein (oxLDL)-mediated lipid accumulation, which was due to an increase in cholesterol efflux. Berberine enhanced the mRNA and protein expression of ATP-binding membrane cassette transport protein A1 (ABCA1) but did not alter the protein level of ABCG1 or other scavenger receptors. Additionally, functional inhibition of ABCA1 with a pharmacological inhibitor or neutralizing antibody abrogated the effects of berberine on cholesterol efflux and lipid accumulation. Moreover, berberine induced the nuclear translocation and activation of liver X receptor α (LXRα) but not its protein expression. Knockdown of LXRα mRNA expression by small interfering RNA abolished the berberine-mediated protective effects on ABCA1 protein expression and oxLDL-induced lipid accumulation in macrophages. These data suggest that berberine abrogates the formation of foam cells by macrophages by enhancing LXRα-ABCA1-dependent cholesterol efflux.

Anti-atherogenic effect of berberine on LXRα-ABCA1-dependent cholesterol efflux in macrophages
https://onlinelibrary.wiley.com/doi/full/10.1002/jcb.22667

Resveratrol, the polyphenol found in grapes and red wine, offers a second angle. It activates SIRT1 and promotes expression of ABCA1 and ABCG1, the transport proteins responsible for exporting cholesterol from macrophages. It also reduces expression of scavenger receptors such as CD36 and SR-A, making macrophages less likely to ingest oxidized LDL in the first place. Animal studies have shown significant reductions in atherosclerotic plaque burden alongside reduced foam-cell formation.

Resveratrol is a type of flavonoids (3,5,40-trihydroxystilbene) found in red wine, berries, and peanuts. This phytochemical can suppress foam cell formation and inhibit atherosclerosis both in vitro and in vivo. Among existing randomized controlled trials, 2000 mg/d is the maximum resveratrol dose with no observed severe adverse effects [79]. A study observed that 10 weeks of resveratrol treatment reduced atherosclerotic lesion size by 38 % and also decreased cholesterol levels in the aortas of apoE-/- mice. Additionally, western blot analysis demonstrated that resveratrol could reduce the expression of scavenger receptors (CD36 and SR-A) and upregulate the expression of cholesterol transporter (ABCA1 and ABCG1). These results indicated that resveratrol could inhibit lipid accumulation in macrophages by modulating cholesterol transporters in apoE-/- mice [80]. In another study, atherosclerotic plaques reduction was observed in both the branchiocephalic arteries and aortic sinus in apoE-/- mice fed a high-fat diet [50]. Resveratrol supplementation inhibited the progression of atherosclerosis. Furthermore, resveratrol suppressed oleate-induced TC and CE accumulation in macrophages by activating PPAR signaling [50].

Phytochemicals alter foam cell formation and macrophage cholesterol efflux
https://www.sciencedirect.com/science/article/pii/S3051307326000027

To complete our trifecta. Curcumin, the principal polyphenol in turmeric, approaches the problem from yet another angle. It suppresses NF-κB, inhibits LOX-1 and CD36 signaling, decreases oxidized LDL uptake and shifts macrophages toward a less inflammatory phenotype. Since chronic inflammation perpetuates foam-cell survival, curcumin may help interrupt that cycle before it becomes self-sustaining.

Treatment with curcumin markedly ameliorated oxidized low-density lipoprotein (oxLDL)-induced cholesterol accumulation in macrophages, which was due to decreased oxLDL uptake and increased cholesterol efflux. In addition, curcumin decreased the protein expression of scavenger receptor class A (SR-A) but increased that of ATP-binding cassette transporter (ABC) A1 and had no effect on the protein expression of CD36, class B receptor type I (SR-BI), or ATP-binding cassette transporter G1 (ABCG1). The downregulation of SR-A by curcumin was via ubiquitin–proteasome–calpain-mediated proteolysis. Furthermore, the curcumin-induced upregulation of ABCA1 was mainly through calmodulin-liver X receptor α (LXRα)-dependent transcriptional regulation. Curcumin administration modulated the expression of SR-A, ABCA1, ABCG1, and SR-BI in aortas and retarded atherosclerosis in apoE−/− mice.

Conclusion

Our findings suggest that inhibition of SR-A-mediated oxLDL uptake and promotion of ABCA1-dependent cholesterol efflux are two crucial events in suppression of cholesterol accumulation by curcumin in the transformation of macrophage foam cells.

Molecular mechanism of curcumin on the suppression of cholesterol accumulation in macrophage foam cells and atherosclerosis
https://onlinelibrary.wiley.com/doi/10.1002/mnfr.201100735

Taken together, these three compounds target nearly every major step in foam-cell biology:

• Reduce uptake of oxidized LDL

• Increase cholesterol efflux through ABCA1

• Decrease oxidative stress

• Suppress chronic inflammatory signaling

• Improve endothelial function

• Support healthier macrophage behavior

This is precisely why they caught my attention. Sometimes the best therapies are those that quietly interrupt pathology before irreversible damage occurs. As I always state, thank you for keeping me going. I appreciate all of your support and am grateful to everyone in our community. Please have a blessed weekend.

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OFCA is characterized by the accumulation of lipid-laden macrophages in the intima causing narrowing. A thin adventitial cuff of fibrous tissue and mononuclear cell infiltration is present. HE staining, ×200. HE: Hematoxylin–Eosin; OFCA: Obliterative foam-cell arteriopathy

Recently, I came across a little-known vascular pathology called Obliterative Foam-Cell Arteriopathy (OFCA). The more I read, the more I wondered whether it might provide a framework for understanding persistent Spike Protein-induced vascular disease, especially since it is at the crossroads of so many Spike Protein-related pathologies.

OFCA is morphologically defined as a localized (single-organ) form of vasculopathy limited to small-sized or medium-sized arteries characterized by accumulation of lipid-laden macrophages in the intima causing narrowing or complete obstruction. OFCA is mainly a disease of the arterial intima. We propose to group a series of previously described entities, such as ionizing radiation arteriopathy, acute atherosis (foam-cell decidual arteriopathy), transplant arteriopathy of solid organ allografts, and intratumoral-associated foam-cell arteriopathy that constitute different manifestations of the same basic morphological process identified as OFCA. The basic mechanism of development of this arteriopathy is endothelial activation and dysfunction (local arterial endotheliopathy).

Obliterative foam-cell arteriopathy. A unifying concept embracing several entities previously described as radiation, decidual, transplant, and intratumoral-associated arteriopathy
https://pmc.ncbi.nlm.nih.gov/articles/PMC10863698/

Look at the last sentence in the above quote. Aren’t “endothelial activation and dysfunction” the quintessence of SPED (Spike Protein Endothelial Disease)?

The elements exist. The Spike activates the endothelium and causes endothelial dysfunction.

Although the use of a noninfectious pseudovirus is a limitation to this study, our data reveals that S protein alone can damage endothelium, manifested by impaired mitochondrial function and eNOS activity but increased glycolysis. It appears that S protein in ECs increases redox stress which may lead to AMPK deactivation, MDM2 upregulation, and ultimately ACE2 destabilization.4 Although these findings need to be confirmed with the SARS-CoV-2 virus in the future study, it seems paradoxical that ACE2 reduction by S protein would decrease the virus infectivity, thereby protecting endothelium. However, a dysregulated renin-angiotensin system due to ACE2 reduction may exacerbate endothelial dysfunction, leading to endotheliitis.

SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2
https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.121.318902

And the Spike Protein activates macrophages.

Results

We found TLR4 to be the most abundantly upregulated TLR in human lung tissue irrespective of the underlying pathology. Accordingly, bronchoalveolar lavage fluid cells from patients with severe COVID-19 showed an NF-κB-pathway dominated immune response, whereas they were mostly defined by type I interferon signalling in moderate COVID-19. Mechanistically, we found the Spike ectodomain, but not receptor binding domain monomer to induce TLR4-dependent inflammation in human macrophages. By using pharmacological inhibitors as well as CRISPR/Cas9 deleted macrophages, we identify SARS-CoV-2 to engage canonical TLR4-MyD88 signalling. Importantly, we demonstrate that TLR4 blockage prevents exaggerated inflammatory responses in human macrophages infected with different SARS-CoV-2 variants, including immune escape variants B.1.1.7.-E484K and B.1.1.529 (omicron).

Conclusion

Our study critically extends the current knowledge on TLR-mediated hyperinflammatory responses to SARS-CoV-2 in human macrophages, paving the way for novel approaches to tackle severe COVID-19.

SARS-CoV-2 activates the TLR4/MyD88 pathway in human macrophages: A possible correlation with strong pro-inflammatory responses in severe COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC10686889/

One finding especially caught my attention that really brought this hypothesis into focus. Investigators discovered that SARS-CoV-2 does not merely activate macrophages—it preferentially infects lipid-laden foam cells within human coronary plaques. Even more striking, infected foam cells produced a robust pro-atherogenic inflammatory response.

Here we show, in coronary autopsy specimens from patients with COVID-19, that infiltrating macrophages were infected by SARS-CoV-2. Lipid-laden macrophages (foam cells), a hallmark of atherosclerosis at all stages of the disease10, were more susceptible to SARS-CoV-2 infection than other macrophages, and this was dependent on the receptor neuropilin-1 (NRP-1). SARS-CoV-2 induced a strong pro-atherogenic inflammatory response in both macrophages and foam cells, which was largely recapitulated in an ex vivo SARS-CoV-2 infection of human vascular explants. This response may contribute to the ischemic cardiovascular complications in patients with COVID-19.

SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels
https://www.nature.com/articles/s44161-023-00336-5

If foam cells themselves can harbor persistent viral material, they may function not simply as markers of vascular injury but as chronic inflammatory reservoirs capable of sustaining endothelial dysfunction long after the acute infection has resolved.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA generally becomes undetectable in upper airways after a few days or weeks postinfection. Here we used a model of viral infection in macaques to address whether SARS-CoV-2 persists in the body and which mechanisms regulate its persistence. Replication-competent virus was detected in bronchioalveolar lavage (BAL) macrophages beyond 6 months postinfection.

SARS-CoV-2 viral persistence in lung alveolar macrophages is controlled by IFN-γ and NK cells
https://www.nature.com/articles/s41590-023-01661-4

Putting all this together, here is what I propose may be occurring:

Persistent Spike Protein
↓
Chronic Endothelial Injury
↓
Oxidative Stress
↓
Oxidized LDL
↓
Foam Cell Formation
↓
IL-6 • ROS • TGF-β
↓
Further Endothelial Injury
↓
Progressive Luminal Narrowing
↓
Microvascular Rarefaction
↓
Chronic Tissue Ischemia

Of course, this remains a hypothesis, but one that is experimentally testable—and, if correct, could help explain the persistent vascular dysfunction observed in Long COVID and what may be occurring to some degree to all exposed to the Spike Protein. Thank you for keeping me going. I appreciate all of your support and am grateful for everyone in our community. Please have a blessed week.

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What’s old is new again.

Danshen, which is also known as Red Sage, is a member of the mint family that has been serving the health of mankind for millennia.

Salvia miltiorrhiza Bunge (S. miltiorrhiza), also known as Danshen (in Chinese) or Dansam (in Korean), is also commonly known as Chinese sage or red sage (Jung, Kim, Moon, Lee, & Kim, 2020). S. miltiorrhiza (SM) Bunge is a perennial plant that belongs to the genus Salvia of the mint family Lamiaceae (Jia et al., 2019). According to Koreans’ original text of the Donguibogam (written in the 17th century), Dansam effectively removes blood stasis and enriches the blood (Jun, 1980). Similarly, in Chinese medicine theory, Danshen helps with blood circulation, clears menstruation, and relieves pain and swelling (Zhou, Zuo, & Chow, 2005). The dried roots of these plants have been used as folk or traditional medicine in Japan, Korea and China for hundreds of years to treat a variety of diseases, such as cancers (Yang, Ju, Jeon, Han, & Shin, 2010), cardiovascular diseases (Sun et al., 2005), liver diseases (Lee et al., 2006), and nervous system diseases (Zhou, Li, Xu, & Chen, 2011). Danshen tea is widely used as a healthy food to prevent coronary heart disease (Shi, Huang, Deng, Wang, & Kai, 2019). There are several types of Danshen preparations for clinical application, including injections, capsules, tablets, granules, medicinal granules and dripping pills (Liu et al., 2015). The Compound Danshen Dripping Pill (CDDP) and Fufang Danshen tablets are the two most famous products (Fang et al., 2014, He et al., 2015, Zhang and Wang, 2006). Notably, Dantonic® (T89, also known as Compound Danshen Dripping Pills) is the first TCM that has completed Phase III clinical trials in the United States.

Review of Danshen: From its metabolism to possible mechanisms of its biological activities
https://www.sciencedirect.com/science/article/pii/S1756464621002620

Danshen, the root and rhizome of Salvia miltiorrhiza Bunge, was one of the earliest and also the most commonly used herbal drug in practice of TCM. The earliest record of Danshen appears to come from the (Shen Nong Materia Medica, A.D. 102–200) E. Han Dynasty. According to the theory of TCM, Danshen is bitter in taste and slightly cold in property, and enters the heart and pericardium meridians. The traditional curative functions are to invigorate blood, remove stagnation, cool blood, reduce carbuncles and clear heat in the heart and soothe irritability (Liu et al., 2000).

Investigation of Danshen and related medicinal plants in China
https://www.sciencedirect.com/science/article/abs/pii/S0378874108005059

What makes this ancient therapeutic new for us, is how it has shown the ability to be effective against the Spike Protein on a number of fronts. First, experimental studies suggest its salvianolic acids can inhibit Spike-mediated viral entry by binding both the Spike receptor-binding domain and ACE2. Access Denied!

Studies have reported that the traditional Chinese medicine Salvia miltiorrhiza possesses remarkable antiviral properties; however, the anti‐coronaviral activity of its main components, salvianolic acid A (SAA), salvianolic acid B (SAB), and salvianolic acid C (SAC) is still debated. In this study, we used Cell Counting Kit‐8 staining and flow cytometry to evaluate the toxicity of SAA, SAB, and SAC on ACE2 (angiotensin‐converting enzyme 2) high‐expressing HEK293T cells (ACE2h cells). We found that SAA, SAB, and SAC had a minor effect on the viability of ACE2h cells at concentrations below 100 μM. We further evaluated the binding capacity of SAA, SAB, and SAC to ACE2 and the spike protein of 2019‐nCoV using molecular docking and surface plasmon resonance. They could bind to the receptor‐binding domain (RBD) of the 2019‐nCoV with a binding constant (K D) of (3.82 ± 0.43) e−6 M, (5.15 ± 0.64)e−7 M, and (2.19 ± 0.14)e‐6 M; and bind to ACE2 with K D (4.08 ± 0.61)e−7 M, (2.95 ± 0.78)e−7 M, and (7.32 ± 0.42)e−7 M, respectively. As a result, SAA, SAB, and SAC were determined to inhibit the entry of 2019‐nCoV Spike pseudovirus with an EC50 of 11.31, 6.22, and 10.14 μM on ACE2h cells, respectively. In conclusion, our study revealed that three Salvianolic acids can inhibit the entry of 2019‐nCoV spike pseudovirus into ACE2h cells by binding to the RBD of the 2019‐nCoV spike protein and ACE2 protein.

Three salvianolic acids inhibit 2019‐nCoV spike pseudovirus viropexis by binding to both its RBD and receptor ACE2
https://pmc.ncbi.nlm.nih.gov/articles/PMC8013543/

For those who have become infected with COVID or have been exposed to the Spike Protein, Danshen may be a strong ally in protecting the endothelium (and the mitochondria), potentially helping protect against the endothelial dysfunction that I have described as SPED (Spike Protein Endothelial Disease).

Through this review, we found that SM has antioxidative, anti-inflammatory, and antithrombotic effects. SM can decrease ROS formation in the mitochondria, preventing endothelial cell dysfunction. Endothelial dysfunction may be related to many cardiovascular and cerebrovascular diseases, such as stroke, acute myocardial infarction, peripheral vascular disease, and Alzheimer’s disease. Both lipophilic and hydrophilic components of SM can protect the endothelium against mitochondrial oxidative stress. More research is needed to discover the mechanism of SM in preventing oxidative stress in the endothelium.

Salvia miltiorrhiza Protects Endothelial Dysfunction against Mitochondrial Oxidative Stress
https://pmc.ncbi.nlm.nih.gov/articles/PMC7179142/

As the Spike Protein is known to activate both NLRP3 and NF- κB inflammatory pathways, Danshen may be useful here too. Danshen has been shown experimentally to suppress activation of both the NF-κB pathway and the NLRP3 inflammasome and ameliorates early atherosclerosis.

Compared with the model group, the SAA (Salvianolic acid A (SAA), an important bioactive polyphenolic acid found in Salvia miltiorrhiza) high dosage (1 mg/kg) group exhibited decreased hemoglobin A1C levels but unchanged blood glucose levels. The disrupted lipid profiles were ameliorated by SAA, with significantly decreased levels of blood cholesterol, LDL-C and triglyceride. The protective effects of SAA against early AS were further confirmed by histopathological examination of aortic tissues. In addition, we observed that SAA decreased serum hs-CRP levels and suppressed the activation of NLRP3 inflammasome and NF-κB signaling in aortic tissues of ZDF rats. Collectively, our results demonstrate the potential of SAA to alleviate AS and T2DM in ZDF rats as a result of its anti-inflammatory effects.

Salvianolic Acid A Ameliorates Early-Stage Atherosclerosis Development by Inhibiting NLRP3 Inflammasome Activation in Zucker Diabetic Fatty Rats
https://pmc.ncbi.nlm.nih.gov/articles/PMC7179142/

One other therapeutic aspect worth mentioning is that a preparation containing both Astragalus membranaceus and Salvia miltiorrhiza significantly improved fatigue and brain fog scores in an observational study of patients with Long COVID. While the contribution of each herb remains uncertain, the results are encouraging and deserve further study.

Results

A total of 50 participants (18 males, 32 females) were enrolled; 49 were included in the intention-to-treat analysis with scores of 66.9 ± 11.7 on mKCFQ11 and 6.3 ± 1.5 on the brain fog VAS. After 4 weeks of MYP (myelophil, a 30% ethanol extract of Astragalus membranaceus and Salvia miltiorrhiza) administration, there were statistically significant improvements in fatigue levels: mKCFQ11 was measured at 34.8 ± 17.1 and brain fog VAS at 3.0 ± 1.9. Additionally, MFI-20 decreased from 64.8 ± 9.8 to 49.3 ± 10.8, fatigue VAS dropped from 7.4 ± 1.0 to 3.4 ± 1.7, SF-12 scores rose from 53.3 ± 14.9 to 78.6 ± 14.3, and plasma cortisol levels also elevated from 138.8 ± 50.1 to 176.9 ± 62.0 /mL. No safety concerns emerged during the trial.

Conclusion

Current findings underline MYP’s potential in managing Long COVID-induced fatigue. However, comprehensive studies remain imperative.

Evaluating myelophil, a 30% ethanol extract of Astragalus membranaceus and Salvia miltiorrhiza, for alleviating fatigue in long COVID: a real-world observational study
https://pmc.ncbi.nlm.nih.gov/articles/PMC11222562/

We have discussed yet another functional nutraceutical which I hope will be investigated further in the context of Long COVID/Spike Protein disease/injury. You keep me going. I appreciate all of your support and am grateful for everyone in our community. Please have a blessed weekend.

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Temporal discounting.

It’s obvious that as a species we are really good at responding to immediate danger; A charging bear. A house fire. A heart attack. These command our full attention since they are immediate threats.

Yet our psychology is generally less responsive to hazards that accumulate gradually over months or years. A danger that unfolds one small step at a time often fails to trigger the same instinctive alarm—even when its cumulative impact may ultimately be substantial.

This phenomenon is well described in psychology and behavioral economics and is known as temporal discounting.

Two experiments were conducted to investigate the effects of a strategic issue’s temporal proximity on the identification of the issue as threatening or opportunity like. In Experiment 1, university students (N = 86) reacted to hypothetical threats or opportunities that differed in the degree to which they were immediate or delayed. Evidence was found for the asymmetrical discounting of strategic issues such that students discounted distant threats more than distant opportunities. In addition, it was found that, although immediate threats were viewed just as likely to occur as immediate opportunities, distant threats were seen as less likely to occur than distant opportunities.

Temporal discounting of strategic issues: Bold forecasts for opportunities and threats
https://pure.psu.edu/en/publications/temporal-discounting-of-strategic-issues-bold-forecasts-for-oppor/

Unsurprisingly, it is why it is so damn difficult for us to change our habits with an eye towards future health.

Normative discounted utility theory specifies that the values of all future outcomes (for example, those related to health and money) should be discounted at a constant rate. Two experiments demonstrated that, contrary to this prescription, decision makers use different discount rates for health-related decisions and money-related decisions. Temporal discount ings for health and money were similar in that both demonstrated two biases previously found in monetary decisions: discount rates were inversely related to magnitude of outcome and length of delay. The relatively large discount rates used by the subjects suggest why it is often difficult to implement preventive health measures that improve future health.

Valuing the Future: Temporal Discounting of Health and Money
https://journals.sagepub.com/doi/abs/10.1177/0272989X9501500408

This may explain why discussions surrounding persistent Spike Protein and Long COVID remain in a state where many – if not most – regard them as nothingburgers.

The MSM has focused solely on acute COVID-19: hospitalization, respiratory failure and immediate mortality. Vaccines were likewise touted primarily for their “ability” to reduce IMMEDIATE severe disease during the acute phase of infection. Sadly. very little has ever been said of COVID sequelae in the MSM. Other than that some people have Long COVID.

No MSM attention has been devoted to an entirely different question:

What if the principal burden of COVID is not an immediate one, but a cumulative biological one?

Many chronic diseases do not emerge overnight.

• Atherosclerosis develops over decades.

• Fibrosis progresses slowly.

• Microvascular dysfunction often begins years before symptoms become obvious.

• Neurodegenerative diseases may silently evolve for decades before diagnosis.

If persistent Spike Protein contributes—even modestly (and you know I believe it to contribute far more so)—to endothelial dysfunction, chronic inflammation, mitochondrial impairment or immune dysregulation, then the resulting disease burden may not appear until years later. Individual effects could be subtle yet repeated over time through multiple infections and Spike Protein exposures; they may gradually accumulate.

Many of the mechanisms we discuss here involved in Long COVID/Spike Protein disease/injury—including endothelial dysfunction, persistent inflammation, oxidative stress, immune dysregulation and mitochondrial impairment—are processes that unfold gradually in chronic diseases rather than catastrophically. Their consequences may only become apparent after years of cumulative injury.

I am certainly not suggesting that persistent Spike Protein is responsible for every chronic illness being investigated today. Much remains uncertain, and careful scientific inquiry is essential.

However, what I am suggesting is that our greatest blind spot may not be biological at all.

It may be psychological.

History repeatedly shows that humanity responds far more readily to crises that explode than to those that slowly unfold. The latter are easier to dismiss because each day’s change appears insignificant—even when the cumulative effect is substantial.

If persistent viral proteins contribute to chronic disease, the challenge before us is not simply one of molecular biology. It is learning to recognize that some of the most consequential threats to human health do not arrive with a bang. They arrive one deleted capillary, one dysfunctional mitochondrion and one inflammatory signal at a time.

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Among nutraceuticals currently under investigation for antiviral, endothelial, mitochondrial and anti-inflammatory effects, cordycepin—the principal bioactive compound of Cordyceps—stands out because many of its reported biological activities overlap with pathways implicated in SARS-CoV-2 and Spike Protein pathology.

Cordyceps is a rare naturally occurring entomopathogenic fungus usually found at high altitudes on the Himalayan plateau and a well-known medicinal mushroom in traditional Chinese medicine. Cordyceps contains various bioactive components, out of which, cordycepin is considered most vital, due to its utmost therapeutic as well as nutraceutical potential. Moreover, the structure similarity of cordycepin with adenosine makes it an important bioactive component, with difference of only hydroxyl group, lacking in the 3′ position of its ribose moiety. Cordycepin is known for various nutraceutical and therapeutic potential, such as anti-diabetic, anti-hyperlipidemia, anti-fungal, anti-inflammatory, immunomodulatory, antioxidant, anti-aging, anticancer, antiviral, hepato-protective, hypo-sexuality, cardiovascular diseases, antimalarial, anti-osteoporotic, anti-arthritic, cosmeceutical etc. which makes it a most valuable medicinal mushroom for helping in maintaining good health.

Cordycepin for Health and Wellbeing: A Potent Bioactive Metabolite of an Entomopathogenic Medicinal Fungus Cordyceps with Its Nutraceutical and Therapeutic Potential
https://pmc.ncbi.nlm.nih.gov/articles/PMC7356751/

Of the SARS-CoV-2/Spike specific benefits of CD, the first I would like to discuss is how CD protects the endothelium. This is particularly relevant because Spike Protein has been shown to suppress SIRT3 expression, while cordycepin has independently been shown to restore SIRT3 signaling and improve endothelial mitochondrial function in experimental models.

The reduction of mitochondrial protein sirtuin protein 3 (SIRT3) has been reported to contribute to the development of T2DM by impacting mitochondrial respiration. Cordycepin is an adenosine derivative and is isolated from the culture filtrate of Cordyceps militaris. This study explored the protective effect of cordycepin on vascular impairment induced by T2DM and its properties and protective mechanism. In this study, a T2DM rat model was established. The endothelium-dependent relaxation of the thoracic aorta ring decreased in T2DM rats could be reversed by cordycepin. Next, mitochondrial impairment in human umbilical vein endothelial cells was detected by JC-1 staining. In vitro studies revealed that cordycepin plays a beneficial role in advanced glycation end product-induced endothelial mitochondrial impairment. Moreover, according to the cordycepin molecular docking analysis, cordycepin can bind to SIRT3. Cordycepin increased the expression and activation of SIRT3 in a dose-dependent manner. SIRT3 interruption blocked the protective effect of cordycepin on mitochondria in human umbilical vein endothelial cells. Cordycepin can conclusively protect vascular function impaired by T2DM, and the mechanism may potentially be involved in SIRT3 signaling pathways.

Protective Effect of Cordycepin on Impairment of Endothelial Function in Type 2 Diabetes Mellitus
https://pubmed.ncbi.nlm.nih.gov/35467807/

We found that spike protein interaction with the epithelium was sufficient to instigate these epithelial responses using a SCV2 spike pseudovirus. Specifically, we found downregulation of the mitochondrial markers SIRT3 and TOMM22. Moreover, SCV2 spike infection increased extracellular acidification and decreased oxygen consumption rate in the epithelium.

SARS-CoV-2 infection alters mitochondrial and cytoskeletal function in human respiratory epithelial cells mediated by expression of spike protein
https://pmc.ncbi.nlm.nih.gov/articles/PMC10470579/

NRP1 is a host receptor utilized by the SARS-CoV-2 Spike Protein and is also instrumental in cancer and syncytial formation in SARS-CoV-2 infection/Spike presence. CD downregulates this, which may be very helpful in fighting cancer, COVID and Spike Protein disease/injury.

As a result, we revealed that CD inhibits NRP1 expressed in cancer cells and prevents viral syncytial formation in 293T-hACE2 cells, implying the therapeutic potential for both anti-cancer and anti-viruses, including anti-SARS-CoV-2. We further found significant associations between NRP1 expressions and the tumor–immune response in immune lymphocytes, chemokines, receptors, immunostimulators, immune inhibitors, and major histocompatibility complexes in most cancer types, implying NRP1’s roles in both anti-cancer and anti-SARS-CoV-2 entry likely via immunotherapy. Importantly, CD also downregulated the expression of NRP1 from lymphocytes in mice and downregulated the expression of A2AR from the lung cancer cell line H1975 when treated with CD, implying the NRP1 mechanism probably through immuno-response pathways. Thus, CD may be a therapeutic component for anti-cancer and anti-viral diseases, including COVID-19, by targeting NRP1 at least.

Natural Product Cordycepin (CD) Inhibition for NRP1/CD304 Expression and Possibly SARS-CoV-2 Susceptibility Prevention on Cancers
https://pmc.ncbi.nlm.nih.gov/articles/PMC10745444/

Because NRP1 has been proposed as a contributor to persistent neurovascular dysfunction in Long COVID, it would be worthwhile to investigate whether cordycepin could serve as an adjunctive therapy in carefully designed clinical trials. At present, this remains a hypothesis requiring clinical validation.

Long coronavirus disease-19 (COVID-19) is a newly discovered syndrome characterized by multiple organ manifestations that persist for weeks to months, following the recovery from acute disease. Occasionally, neurological and cardiovascular side effects mimicking long COVID-19 have been reported in recipients of COVID-19 vaccines. Hypothetically, the clinical similarity could be due to a shared pathogenic role of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike (S) protein produced by the virus or used for immunization. The S protein can bind to neuropilin (NRP)-1, which normally functions as a coreceptor for the vascular endothelial growth factor (VEGF)-A. By antagonizing the docking of VEGF-A to NRP-1, the S protein could disrupt physiological pathways involved in angiogenesis and nociception. One consequence could be the increase in unbound forms of VEGF-A that could bind to other receptors. SARS-CoV-2-infected individuals may exhibit increased plasma levels of VEGF-A during both acute illness and convalescence, which could be responsible for diffuse microvascular and neurological damage.

Impaired VEGF-A-Mediated Neurovascular Crosstalk Induced by SARS-CoV-2 Spike Protein: A Potential Hypothesis Explaining Long COVID-19 Symptoms and COVID-19 Vaccine Side Effects?
https://pmc.ncbi.nlm.nih.gov/articles/PMC9784975/

Downregulation of NRP1 represents one plausible mechanism by which cordycepin could exert beneficial effects, although multiple pathways—including mitochondrial protection, anti-inflammatory signaling and endothelial support—are also likely to contribute.

Taken together, the evidence suggests cordycepin acts on several biological systems that repeatedly emerge in SARS-CoV-2 research: endothelial dysfunction, mitochondrial impairment, chronic inflammation and NRP1 signaling. While none of these studies demonstrates efficacy in Long COVID patients directly, the convergence of these mechanisms makes cordycepin an intriguing candidate for further translational and clinical investigation.

As always, please remember this is a work of medical research and not medical advice. Make certain to talk with your primary care provider before using any medication or supplement.

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A Oxidative phosphorylation (OXPHOS) capacity was significantly lower in patients with long COVID (n = 25) compared to healthy controls (n = 21), and remained lower one day after induction of post-exertional malaise (PEM) in patients (Group: p = 0.003, Time: p < 0.001). B Succinate dehydrogenase (SDH) activity, a marker for mitochondrial density, was not different between groups (p = 0.06) and only reduced (p = 0.0083) after induction of post-exertional malaise in long COVID patients (n = 25) compared to healthy controls (n = 21). A typical example of the SDH activity is shown in panel C. Skeletal muscle (D) and venous (E) metabolome pathways indicate slightly higher levels of metabolites related to glycolysis, and a lower abundance of metabolites related to purine synthesis and the tricarboxylic acid (TCA) cycle, indicative of a lower reliance on oxidative metabolism in patients with long COVID (n = 25, both timepoints) as compared to healthy (n = 19, both timepoints). Faded names were not measured and shown for clarity. A higher effect size in long COVID is shown in red, lower effect size in blue. Continuous parametric longitudinal data (panels A, B, D, E) were analyzed with a generalized linear mixed model with a two-sided ANOVA. Post-hoc tests comparing each group were performed when the interaction term was significant and was performed using emmeans with BH adjustment (panels A and B). Effect sizes (D and E) were calculated with Hedges‘ g *p < 0.05; **p < 0.001; †p < 0.05 indicates a significant interaction effect. Bar: 50 μm. PEM post-exertional malaise. Box plots show the median (centerline), the first and third quartiles (the lower and upper bound of the box), and the whiskers show the 1.5× interquartile range.

Last week we discussed evidence supporting the hypothesis that the presence of the Spike Protein causes persistent microvascular destruction. This week I would like to discuss how that same persistence may be responsible for the debilitating fatigue experienced by those with Long COVID.

Fatigue is almost certainly the most common persistent symptom of Long COVID.

Fatigue was reported as one of the most common persistent symptoms in individuals infected with SARS-CoV-2 before. Persistent fatigue lasting at least 6 months is termed chronic fatigue syndrome (33). This may be observed after several viral and bacterial infections (48). In the included studies of the present systematic review, fatigue was a symptom that either occurred already in the acute phase or developed after recovery from the acute phase of infection. The included studies recruited patients for a maximum of 9 months, with fatigue as persistent symptom. This should be followed up for a longer period to see how long fatigue could persist after the acute infection of COVID-19.

Post-COVID-19 fatigue: A systematic review
https://pmc.ncbi.nlm.nih.gov/articles/PMC9403611/

Mitochondrial dysfunction is the primary driver of Chronic Fatigue Syndrome symptoms.

Our observations strongly implicate mitochondrial dysfunction as the immediate cause of CFS symptoms. However, we cannot tell whether the damage to mitochondrial function is a primary effect, or a secondary effect to one or more of a number of primary conditions, for example cellular hypoxia [30], or oxidative stress including excessive peroxynitrite [54-58]. Mitochondrial dysfunction is also associated with several other diseases and this is not surprising in view of the important role of mitochondria in almost every cell of the body, but this fact appears to have been recognised only in recent years [34, 38, 59, 60].

Chronic fatigue syndrome and mitochondrial dysfunction
https://pmc.ncbi.nlm.nih.gov/articles/PMC2680051/

As with many other viral diseases, SARS-CoV-2 causes viral mitochondriopathy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), disrupts cellular mitochondria, leading to widespread chronic inflammation and multi-organ dysfunction. Viral proteins cause mitochondrial bioenergetic collapse, disrupt mitochondrial dynamics, and impair ionic homeostasis, while avoiding antiviral defenses, including mitochondrial antiviral signaling. These changes drive both acute COVID-19 and its longer-term effects, known as “long COVID”.

Viral mitochondriopathy in COVID-19
https://www.sciencedirect.com/science/article/pii/S2213231725002794

However, in the case of Long COVID/Spike Protein disease/injury, the Spike Protein itself may be the primary driving cause of the debilitating mitochondrial-based fatigue – along with perhaps a vast majority of the symptoms.

The 24 h S1 treatment increased ATP production and mitochondrial respiration by increasing the expression of fatty-acid-transporting regulators and inducing more negative mitochondrial membrane potential (Δψm). The 72 h S1 treatment decreased mitochondrial respiration rates and Δψm, but increased levels of reactive oxygen species (ROS), mCa2+, and intracellular Ca2+. Electron microscopy revealed increased mitochondrial fragmentation/fission in AC16 cells treated for 72 h. The effects of S1 on ATP production were completely blocked by neutralizing ACE2 but not CD147 antibodies, and were partly attenuated by Mitotempo (1 µM). Conclusion: S1 might impair mitochondrial function in human cardiomyocytes by altering Δψm, mCa2+ overload, ROS accumulation, and mitochondrial dynamics via ACE2.

Spike Protein Impairs Mitochondrial Function in Human Cardiomyocytes: Mechanisms Underlying Cardiac Injury in COVID-19
https://pmc.ncbi.nlm.nih.gov/articles/PMC10046940/

As we have discussed several times before, Spike Protein is circulating freely in those with Long COVID.

Compared to people who didn’t report long COVID symptoms, those who reported persisting symptoms affecting many organ systems were approximately twice as likely to have SARS-CoV-2 proteins circulating in their blood. The research team was able to detect the spike protein and other components of the SARS-CoV-2 virus using Simoa, an ultrasensitive test for detecting single molecules. Commonly reported long COVID symptoms included fatigue, brain fog, muscle pain, joint pain, back pain, headache, sleep disturbance, loss of smell or taste, and gastrointestinal symptoms.

Study Finds Persistent Infection Could Explain Long COVID in Some People
https://www.massgeneralbrigham.org/en/about/newsroom/press-releases/study-finds-persistent-infection-could-explain-long-covid-in-some-people

To conclude, I will present evidence that bridges last week’s post and this week’s. Muscle biopsies found that in those with Long COVID BOTH microvascular destruction and mitochondrial dysfunction were occurring simultaneously.

Succinate dehydrogenase (SDH) activity (a marker for mitochondrial content) correlated with V̇O2max in healthy controls, but not in patients (Fig. 2F). While patients had a significantly lower oxidative phosphorylation capacity (Fig. 3A, ED 5A–H), no differences were observed in SDH activity (Fig. 3B, C; Supplemental Fig. 5I, J), suggestive of qualitatively lower mitochondrial respiration rather than a lower mitochondrial enzyme activity. Collectively, our data indicate that the lower exercise capacity in long COVID patients is associated with a greater proportion of high-fatigable glycolytic fibers and lower mitochondrial function, with a possible additional limitation of a lower capillarization and the ventilatory system.

Muscle abnormalities worsen after post-exertional malaise in long COVID
https://www.nature.com/articles/s41467-023-44432-3

If persistent Spike Protein contributes both to progressive microvascular injury and impaired mitochondrial respiration, it could create a particularly damaging combination: reduced oxygen delivery together with reduced cellular ability to utilize oxygen efficiently. That combination could help explain why fatigue in Long COVID can be so profound.

I will continue to research these mechanisms while striving to discover how the Spike’s inflammatory perspective fits into all of this. Great thanks for the gnenerous donation received since Friday. You keep me going. I appreciate it and am thankful to everyone in our community. Please have a blessed week.

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