Long-Covid, viruses, ‘zombie’ cells: New research looks for links to chronic fatigue, brain fog

By Burtram C Fielding, Etheresia Pretorius and Massimo Nunes for The Conversation

Stellenbosch, South Africa: 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.

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.

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.

Immune exhaustion locks in the damage

Some parts of the immune system kill senescent cells. They are natural-killer cells, macrophages and complement proteins, which are immune molecules capable of tagging and killing pathogens. But long-Covid and ME/CFS frequently have impaired natural-killer cell function, sluggish macrophages and complement dysfunction.

Senescent endothelial cells may also send out a chemical signal to repel immune attack. So the “zombie cells” actively evade the immune system. This creates a self-sustaining loop of vascular and immune dysfunction, where senescent endothelial cells persist.

In a healthy person with an optimally functioning immune system, these senescent endothelial cells will normally be cleared. But there is significant immune dysfunction in ME/CFS and long-Covid, and this may enable the “zombie cells” to survive and the disease to progress.

Where the research goes next

There is a registered clinical trial in the US that is investigating senescence in long-Covid. Our consortium is testing new ways to spot signs of ageing in the cells that line our blood vessels. First, we expose healthy endothelial cells in the lab to blood from patients to see whether it pushes the cells into a senescent, or “zombie,” state.

At the same time, we are trialling non-invasive imaging and fluorescent probes that could one day reveal these ageing cells inside the body. In selected cases, tissue biopsies may later confirm what the scans show. Together, these approaches aim to pinpoint how substances circulating in the blood drive cellular ageing and how that, in turn, fuels disease.

Our aim is simple: find these ageing endothelial cells in real patients. Pinpointing them will inform the next round of clinical trials and open the door to therapies that target senescent cells directly, offering a route to healthier blood vessels and, ultimately, lighter disease loads.

(Burtram C Fielding is a Dean Faculty of Sciences and Professor in the Department of Microbiology, Stellenbosch University, Etheresia Pretorius is a Distinguished Professor in Physiological Sciences, Stellenbosch University and Massimo Nunes is a Postdoctoral Research Fellow , Stellenbosch University.)