Preprint Virus-Induced Endothelial Senescence as a Cause and Driving Factor for ME/CFS and Long COVID: Mediated by a Dysfunctional Immune System, 2025, Nunes +

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Virus-Induced Endothelial Senescence as a Cause and Driving Factor for ME/CFS and Long COVID: Mediated by a Dysfunctional Immune System


Massimo Nunes, Loren Kell, Anouk Slaghekke, Rob Wüst, Burtram Fielding, Douglas Kell, Etheresia Pretorius

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID are two post-viral diseases, which share many common symptoms and pathophysiological alterations. Yet a mechanistic explanation of disease induction and maintenance is lacking. This hinders the discovery and implementation of biomarkers and treatment options, and ultimately the establishment of effective clinical resolution.

Here, we propose that acute viral infection results in (in)direct endothelial dysfunction and senescence, which at the blood-brain barrier, cerebral arteries, gastrointestinal tract, and skeletal muscle can explain symptoms. The endothelial senescence-associated secretory phenotype (SASP) is proinflammatory, pro-oxidative, procoagulant, primed for vasoconstriction, and characterized by impaired regulation of tissue repair, but also leads to dysregulated inflammatory processes. Immune abnormalities in ME/CFS and long COVID can account for the persistence of endothelial senescence long past the acute infection by preventing their clearance, thereby providing a mechanism for the chronic nature of ME/CFS and long COVID.

The systemic and tissue-specific effects of endothelial senescence can thus explain the multisystem involvement in and subtypes of ME/CFS and long COVID, including dysregulated blood flow and perfusion deficits. This can occur in all tissues, but especially the brain as evidenced by findings of reduced cerebral blood flow and impaired perfusion of various brain regions, post-exertional malaise (PEM), gastrointestinal disturbances, and fatigue. Paramount to this theory is the affected endothelium, and the bidirectional sustainment of immune abnormalities and endothelial senescence.

The recognition of endothelial cell dysfunction and senescence as a core element in the aetiology of both ME/CFS and Long COVID should aid in the establishment of effective biomarkers and treatment regimens.

Link (preprints.org) [not peer reviewed]

https://doi.org/10.20944/preprints202505.1875.v1
 
I think this theory fails due to PWME reporting developing the disease without having an acute viral infection.

I don't know how rapidly the proposed mechanism acts. Could it explain the abrupt switching of state (full ME to full not-ME within minutes)?

It seems testable by measuring cerebral blood flow in patients with different severities, and PEM vs not-PEM.
 
As members of the subset of ME patients with sudden viral onset, many of us could benefit from research that focuses on postviral ME and Long COVID.

I do wonder about this research being "pre-publication" for a couple of months now, and not being peer reviewed.
 
Millions of people who recover from infections like COVID-19, influenza and glandular fever are affected by long-lasting symptoms. These include chronic fatigue, brain fog, exercise intolerance, dizziness, muscle or joint pain and gut problems. And many of these symptoms worsen after exercise, a phenomenon known as post-exertional malaise.
Medically the symptoms are known as myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). The World Health Organization classifies this as a post viral fatigue syndrome, and it is recognised by both the WHO and the United States Centers for Disease Control and Prevention as a brain disorder.

Experiencing illness long after contracting an infection is not new, as patients have reported these symptoms for decades. But COVID-19 has amplified the problem worldwide. Nearly half of people with ongoing post-COVID symptoms – a condition known as long-COVID – now meet the criteria for ME/CFS. Since the start of the pandemic in 2020, it is estimated that more than 400 million people have developed long-COVID.


To date, no widely accepted and testable mechanism has fully explained the biological processes underlying long-COVID and ME/CFS. Our work offers a new perspective that may help close this gap.
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Our research group studies blood and the cardiovascular system in inflammatory diseases, as well as post-viral conditions. We focus on coagulation, inflammation and endothelial cells. Endothelial cells make up the inner layer of blood vessels and serve many important functions, like regulating blood clotting, blood vessel dilation and constriction, and inflammation.

Our latest review aims to explain how ME/CFS and long-COVID start and progress, and how symptoms show up in the body and its systems. By pinpointing and explaining the underlying disease mechanisms, we can pave the way for better clinical tools to diagnose and treat people living with ME/CFS and long-COVID.

What is endothelial senescence?​

In our review, our international team proposes that certain viruses drive endothelial cells into a half-alive, “zombie-like” state called cellular senescence. Senescent endothelial cells stop dividing, but continue to release molecules that awaken and confuse the immune system. This prompts the blood to form clots and, at the same time, prevent clot breakdown, which could lead to the constriction of blood vessels and limited blood flow.
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By placing “zombie” blood-vessel cells at the centre of these post-viral diseases, our hypothesis weaves together microclots, oxygen debt (the extra oxygen your body needs after strenuous exercise to restore balance), brain-fog, dizziness, gut leakiness (a digestive condition where the intestinal lining allows toxins into the bloodstream) and immune dysfunction into a single, testable narrative.

From acute viral infection to ‘zombie’ vessels​

Viruses like SARS-CoV-2, Epstein–Barr virus, HHV-6, influenza A, and enteroviruses (a group of viruses that cause a number of infectious illnesses which are usually mild) can all infect endothelial cells. They enable a direct attack on the cells that line the inside of blood vessels. Some of these viruses have been shown to trigger endothelial senescence.


Multiple studies show that SARS-CoV-2 (the virus which causes COVID-19 disease) has the ability to induce senescence in a variety of cell types, including endothelial cells. Viral proteins from SARS-CoV-2, for example, sabotage DNA-repair pathways and push the host cell towards a senescent state, while senescent cells in turn become even more susceptible to viral entry. This reciprocity helps explain why different pathogens can result in the same chronic illness. Influenza A, too, has shown the ability to drive endothelial cells into a senescent, zombie-like state.

What we think is happening​

We propose that when blood-vessel cells turn into “zombies”, they pump out substances that make blood thicker and prone to forming tiny clots. These clots slow down circulation, so less oxygen reaches muscles and organs. This is one reason people feel drained.

During exercise, the problem worsens. Instead of the vessels relaxing to allow adequate bloodflow, they tighten further. This means that muscles are starved of oxygen and patients experience a crash the day after exercise. In the brain, the same faulty cells let blood flow drop and leak, bringing on brain fog and dizziness.


In the gut, they weaken the lining, allowing bits of bacteria to slip into the bloodstream and trigger more inflammation. Because blood vessels reach every corner of the body, even scattered patches of these “zombie” cells found in the blood vessels can create the mix of symptoms seen in long-COVID and ME/CFS.
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This article is republished from The Conversation under a Creative Commons license. Read the original article.
 
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