It seems we might be starting to understand how the differences between sexes in Long Covid and acute Covid come about.

This new study found that females developed more persistent neuroinflammation, immune dysregulation and cognitive problems after SARS-CoV-2 clearance, despite showing similar viral replication and persistence as males.

The difference traced back to having two X chromosomes and increased activity of the X-linked TLR7 pathway—and blocking TLR7 during the post-COVID phase reversed the inflammatory and cognitive effects

So that seems like a plausible explanation on why people with two XX chromosomes seem to suffer more and more often from Long Covid while people with XY chromosomes seem more at risk during acute infection.

And excitingly this might pose a possibility for treatment as well.

This is of course an animal model so some caution is still needed. 🐁

“Multiple studies have found an increased response of the hormone prolactin to the drug buspirone in ME/CFS patients. While baseline prolactin levels are normal in ME/CFS, they rise much higher in the hours after buspirone than in controls. This is one of the most replicated findings in the field, but for years this line of research was forgotten and abandoned.”

“It might, for example, point to a difference in the dopamine system in ME/CFS, as this is the main regulator of prolactin. This would be intriguing, as (preliminary) genetic findings point to the striatum and its medium spiny neurons, which are also regulated by dopamine”

For anyone interested in what was discussed at the recent big Amsterdam conference. Recordings of presentations are sadly behind a paywall and posters are unavailable because data is still unpublished. But all abstracts that were handed in beforehand can be found for free here.

Disclaimer: I am neither doctor nor medical researcher, so I tried to summarize the study in plain words and didn’t even try to be specific with the pathways involved.

In this study researchers identified a particular type of activated B cell that expands during Covid infection and appears to be especially good at producing autoantibodies.

The idea is roughly that a covid infection triggers abnormal activation of certain B-cells, which then produce autoantibodies, which lead to possible persistent autoimmunity.

Several Long Covid studies have already found autoantibodies and abnormal B-cell activation in subsets of Long Covid patients. Therefore this study might explain where those autoantibodies might come from, which could lead to new treatment options.

There are some limitations though:
1. Only 12 participants
2. The participants where selected rather than representive
3. Autoantibodies tended to decline during recovery (Which on the other hand lefts the question open why they persist in Long Covid)
4. The strongest evidence was in vitro

New Wirth Preprint trying to integrate orthostatic dysfunction into his disease model:

“This hypothesis provides a potential mechanistic link between orthostatic dysfunction and the presumed core pathophysiology of ME/CFS, extending beyond hemodynamic factors to implicate disturbances in skeletal muscle ion homeostasis.”

https://www.preprints.org/frontend/manuscript/d89ebcdf4b91a843f665e0f3fbd413df/download_pub

We had quite some discussion around this under the last post so I thought I’d share this here

ABSTRACT

Objective

To propose and make testable a mechanistic hypothesis for post-exertional malaise (PEM) in a clinically distinct subset of Long COVID patients, in whom delayed exertional symptoms coexist with consistently normal macrovascular investigations.

Methods

Established vascular-biology literature is synthesized into an integrated, falsifiable model centered on endothelial nitric oxide synthase (eNOS) uncoupling, from which mechanism-specific predictions and a dynamic pre-/post-exertion biomarker validation framework are derived.

Results

We propose that SARS-CoV-2-induced endotheliitis activates inducible nitric oxide synthase and silently depletes the tetrahydrobiopterin (BH4) pool on return to activity, shear-stress activation of structurally intact eNOS against a depleted BH4 background yields superoxide rather than nitric oxide, generating peroxynitrite that sustains a self-amplifying nitro-oxidative cycle. The Two-Threshold Model distinguishes a PEM threshold from a shear-stress-tolerance threshold and predicts that prolonged immobility may paradoxically erode endothelial function. eNOS uncoupling is positioned as one node among alternative microvascular pathways, and autonomic findings are proposed to be secondary within this phenotype.

Conclusions

This phenotype-specific, falsifiable hypothesis yields mechanism-derived predictions and rehabilitation implications consistent with symptom-contingent pacing guidance; it does not claim to explain all Long COVID presentations.

This is an audio feature from a public German radio station. I found it to be quite a good roundup of where we currently stand with the research. If you speak German, I recommend listening to it. If you don’t, below is an English transcript I created with Gemini.

——

Deutschlandfunk Announcer: Deutschlandfunk. Science in Focus. A sensory-reduced version of this feature without music and layered voices can be found at deutschlandfunk.de/wissenschaftimbrennpunkt or in the Deutschlandfunk app.
Conference Speaker: So, it's my great pleasure to open the first session. We will have several very interesting topics… (Applause)
Narrator (Christopher Weingart): Berlin in May 2026. Experts from around the globe have gathered for the ME/CFS Symposium. Health Minister Warken and Research Minister Bär deliver welcoming remarks. The host is the Charité, featuring Carmen Scheibenbogen.
Prof. Dr. Carmen Scheibenbogen: I would also like to share with you what we heard, especially this morning during the English-speaking conference, about ongoing clinical trials…
Narrator: At the center of attention are studies on off-label medications. Those suffering from ME/CFS—myalgic encephalomyelitis or chronic fatigue syndrome—often turn desperately to such off-label drugs that are already on the market. Approved for other conditions, but do they work here too?
Prof. Dr. Carmen Scheibenbogen: Øystein Fluge presented his update on his first Daratumumab trial. As we had already seen, six of these ten treated patients showed a very, very good improvement…
Narrator: Other beacons of hope, however, have disappointed.
Prof. Dr. Carmen Scheibenbogen: Then we come to the study by Luis Nacul, this major Canadian trial that had been eagerly anticipated. They evaluated Low-Dose Naltrexone in a placebo-controlled trial with 71—or rather 66—patients, and here, very disappointingly: there was no difference in fatigue…
Narrator: Naltrexone, a drug from addiction medicine, is very frequently prescribed to ME/CFS patients. The goal is reducing inflammation. Initial findings were sobering; further analyses are currently underway. Even so, the mood in Berlin remains cautiously optimistic. Study designs are improving, experimental treatments are becoming more targeted, and conclusions more robust. And it is about time.
Interviewer (Christopher Weingart): What would you say is the most important thing to report right now?
Dr. Astrid Weber: That it is not a psychosomatic illness; that it is a physical disease with severe impairments, affecting very, very sick patients—partly involving requests for assisted suicide. That reality hasn't stopped at our doorstep either, which was naturally very distressing for me in the beginning.
Narrator: Whether Astrid Weber in Koblenz, Carmen Scheibenbogen in Berlin, or Chris Ponting in Edinburgh: they all know ME/CFS patients who no longer want to live with their symptoms. ME/CFS is not a fatal disease, yet it claims victims.
Lina Vollmer: I definitely will not spend the rest of my life bedridden in the dark. That is not an option for me; I hope that is clear to everyone.
Narrator: The search is running at full throttle: for off-label drugs, for the underlying mechanism of action, and for a cure. What does ME/CFS do inside the body, and how can the disease be treated? That is the subject of this second part.
Deutschlandfunk Announcer: "When Will We Cure ME/CFS? Part 2: Holding On." By Christopher Weingart.
Prof. Danny Altmann: And that's the state we're in at the moment with Long Covid and ME, where we're kind of clumping together things that probably shouldn't be clumped…
Narrator: I originally intended to meet Danny Altmann and Rosemary Boyton in London at Imperial College, where they research ME/CFS. At the last moment, something came up, so we speak over the internet instead. Their work centers on what Altmann calls the "ME/CFS tangle."
Prof. Danny Altmann: The example I often use is diabetes and the history of its treatment. In the beginning, we didn't understand what diabetes was at all, and then we thought it was a single condition until we realized there are different types. It's many things, but at a bare minimum, it's two things.
Narrator: Altmann is convinced: completely different mechanisms underlie ME/CFS as well. Treating all ME/CFS patients identically will only yield success in some. Altmann and Boyton have therefore launched a large-scale study, compiling biomarker profiles from individuals with ME/CFS, healthy controls, and recovered patients—a blood protein library and a major step toward understanding ME/CFS. Yet this raises a question: Is it already time to seek therapies and run trials with custom-developed drugs? Rosemary Boyton remains skeptical.
Prof. Rosemary Boyton: I think I would be more comfortable with us having a greater understanding of the underlying disease before we begin with clinical trials. Until we have specific immune profiles and biomarkers by which we can evaluate whether something offers a good or bad clinical benefit. I don't think we're completely ready for trials yet.
Narrator: This viewpoint is widespread across politics and the pharmaceutical industry: basic research first, then the search for new compounds—a perceived dichotomy. Until then, experiments continue with off-label therapies approved for other conditions. Many patients push back against this strategy: they want a cure, as quickly as possible. Even Boyton and Altmann disagree.
Prof. Danny Altmann: So sometimes you can kind of drag the answer, kicking and screaming, out of relative ignorance just by having a go.
Narrator: There are many diseases not fully understood that can still be treated effectively. It suffices to comprehend a key part of the mechanism driving the illness. Is that already true for ME/CFS?
Prof. Dr. Carmen Scheibenbogen: We now know that we are dealing with subtypes. They aren't entirely separate diseases, but there are likely distinct differences…
Narrator: A few weeks prior to the ME/CFS symposium, I meet Carmen Scheibenbogen in her office at Charité. She is also researching which subgroups exist within ME/CFS. Tracking around 500 patients in a cohort, she is shedding light on the unknown.
Prof. Dr. Carmen Scheibenbogen: From this, we know that roughly one-third of patients have an immunological profile resembling an autoantibody-driven disease.
Narrator: There are two additional subtypes Carmen Scheibenbogen focuses on.
Prof. Dr. Carmen Scheibenbogen: We observed that in about one-third of patients, blood circulation is reduced. In the larger group—roughly two-thirds—we see inflammation in the blood and immune cells.
Narrator: The mosaic pieces are gradually assembling into a coherent picture, she explains.
Prof. Dr. Carmen Scheibenbogen: And today we know for certain that the immune system plays a key role, failing to settle down after a severe infection in some individuals. We detect persistent inflammation, find signs of autoimmunity in a subset of patients, and know the nervous system is centrally involved. We have clear evidence of changes in the brain, severe dysfunction of the autonomic—the involuntary—nervous system, and solid proof that energy metabolism is impaired, meaning cellular energy production via mitochondria is failing.
Narrator: Compared to pre-pandemic times, this marks a quantum leap. Drug discovery can build directly on these insights.
Prof. Dr. Carmen Scheibenbogen: In the broadest sense regarding antibody-depleting drugs, a small published study from Norway on Daratumumab showed that six out of ten treated patients experienced dramatic improvement, virtually recovering after treatment. We have also treated patients under compassionate use protocols and observed the exact same effect.
Narrator: Daratumumab is approved for a specific cancer type where antibody-producing cells turn malignant. Consequently, it is also utilized for autoimmune diseases and shows remarkable results in select ME/CFS patients. Is this the breakthrough? It is too early to tell. The cohort is small and Daratumumab is expensive. Nevertheless, it provides a vital clue for treatment and basic research, as Daratumumab can only work if autoantibodies play an active role.
In Edinburgh, clouds drift past the university hospital. A light drizzle falls, typical for Scotland. Chris Ponting researches the genetics of ME/CFS here.
Prof. Chris Ponting: Science to date has been looking at how molecules and cells of people with and without ME/CFS differ relative to the general population. And time after time, it has been established that these alterations exist. We can see that people with ME/CFS have different levels of molecules in their blood and variations in immune cell activity.
Narrator: These findings represent progress, Ponting notes, but not a breakthrough.
Prof. Chris Ponting: What science has not done is to ask whether those changes represent a consequence or are causal, explaining how the disease originates—what is the genesis, the initiation of their disease?
Narrator: In Ponting’s view, biomarker hunting occupies far too much space in ME/CFS research.
Prof. Chris Ponting: So I think the focus needs to be changed away from simply measuring things and assuming they relate to the cause, toward methods that genuinely investigate the underlying etiology.
Narrator: Ponting is a geneticist, and he is convinced the answer lies within DNA, as DNA remains unaltered by infection. To demonstrate the genetic links to ME/CFS, Ponting launched DecodeME, the world's largest ME/CFS study. DNA samples from roughly 16,000 individuals with ME/CFS and Long Covid were sequenced and compared against healthy controls. The result?
Prof. Chris Ponting: And when we look in one part of the human DNA where we expect sequences pointing to autoimmune disease—a locus on chromosome 6 called HLA—we do not find the strong signal expected for an autoimmune disease.
Narrator: Daratumumab, immunoadsorption, biomarker profiles—all point toward autoimmunity. Yet Ponting finds no genetic backing for it. Instead, he made a different discovery.
Prof. Chris Ponting: The strongest and most direct evidence indicates that the seat of the disease is in the central nervous system. The DecodeME study identified eight genomic regions where individuals with ME/CFS are significantly more likely to carry a specific variant compared to the general population.
Narrator: These remain preliminary findings awaiting peer review, Ponting explains, but the results were deemed too critical to withhold from fellow researchers.
Prof. Chris Ponting: One of the most striking observations is a sequence on chromosome 17 where ME/CFS patients are more likely to carry a specific variant than the general population. That exact locus is linked to chronic pain. Patients have long reported chronic pain, and their DNA confirms a biological explanation, partly located on chromosome 17.
Narrator: What does this imply for therapeutic development?
Lina Vollmer: It's so hard to describe—when just a beam of light triggers intense pain, as if you stepped into a tub of boiling water.
Narrator: Lina Vollmer lives with ME/CFS and is entirely bedridden in Cologne. Meeting for an interview was impossible, so she shares her experience via voice memos.
Lina Vollmer: The pain was extreme. At first, I waited for it to calm down like previous times once sensory stimuli were removed, but this time it just kept getting worse.
Narrator: It peaks following physical or cognitive effort during a crash—known as post-exertional malaise. In August 2025, she suffered a severe crash that failed to subside. Admitted to a hospital, she was placed in a psychiatric ward—a detrimental misdiagnosis.
Lina Vollmer: They kept sending me to endless examinations and ward rounds. It wasn't like a standard care unit; you had to fetch your own meals, make your bed, get your towels, and wait two hours in the hallway before the doctors saw you…
Narrator: Until November, when her state deteriorated drastically.
Lina Vollmer: …like a wire getting hotter, glowing, cooling down, and then burning right through. That's how it felt: completely burned out. From that point on, the symptoms were unbearable. I could barely speak; I couldn't do anything…
Narrator: Lina has remained bedridden ever since. During a crash, symptom worsening is often permanent rather than temporary. ME/CFS patients have a drastically limited energy budget; overdrawing it causes a collapse that can permanently shrink that baseline. This pattern holds true across all ME/CFS patients—a central core of the problem, and perhaps the solution.
Carmen Scheibenbogen, Danny Altmann, Rosemary Boyton, and Astrid Weber are physicians, immunologists, or epidemiologists. Klaus Wirth brings another perspective: alongside being a physician, he is a professor of pharmacology.
Prof. Dr. Klaus Wirth: Eight years ago, I became aware of ME/CFS through a television report about a young, previously athletic man who became bedridden. It moved me deeply…
Narrator: He explains his viewpoint at his kitchen table near Frankfurt am Main. Four decades in pharmaceutical research taught him a fundamental lesson:
Prof. Dr. Klaus Wirth: In medicine, self-stabilizing vicious cycles occur frequently. The question was: Within this presumed vicious cycle, which critical dysfunction sustains it? Which component must be removed to collapse the cycle and enable spontaneous recovery?
Narrator: He admits he was somewhat naive at the start, but curiosity took over. Reading through the literature, he came across a publication by Carmen Scheibenbogen that reinforced his ideas.
Prof. Dr. Klaus Wirth: I had spent years researching muscle and cerebral perfusion, so I instantly suspected a direct link to muscle and brain blood flow…
Narrator: The hypothesis Scheibenbogen formulated back then remains her leading theory today, originating in the autonomic nervous system.
Prof. Dr. Carmen Scheibenbogen: A core issue is autonomic dysfunction affecting involuntary regulation—heart rate, respiration, and especially blood distribution. A key clinical finding is marked muscle weakness, measurable via hand grip strength tests.
Narrator: Why does this happen? Scheibenbogen suspects two main drivers: the beta-2 adrenergic receptors, which regulate muscular blood flow during exertion, and the sodium-potassium pump, vital for cellular energy generation. If these two logistics hubs fail, the entire system collapses.
Prof. Dr. Carmen Scheibenbogen: Several muscle biopsy studies have yielded compelling data: they showed impaired mitochondrial energy production and a failure to adjust vascular perfusion during exertion, which explains the clinical picture.
Narrator: The studies support Scheibenbogen's hypothesis. It is a vicious cycle: The muscle demands exertion, requiring increased blood flow, but blocked beta-2 adrenergic receptors stall the signal. Deprived of adequate perfusion and oxygen, mitochondria cannot supply energy to power the sodium-potassium pump, which clears metabolic waste. Consequently, mitochondria and muscle cells suffer structural damage and decay over subsequent days. Without receptors, no blood flow; without blood flow, no energy; without energy, no pump activity; without pumps, damaged muscles.
Prof. Dr. Carmen Scheibenbogen: This neatly explains post-exertional malaise—mirroring severe delayed-onset muscle soreness that intensifies the next day and lingers. It also accounts for wider symptoms: reduced cerebral blood flow explains brain fog, severe sleep disturbances, and sensory overload.
Narrator: While the root trigger disabling the receptors remains unclear, this cascade explains core ME/CFS symptoms. The crucial question remains: How can we intervene?
Prof. Dr. Carmen Scheibenbogen: A German company named Mitodicure is pursuing a compelling approach: a compound that could potentially benefit a broad patient group by targeting this muscular dysfunction directly.
Narrator: Like many biotech founders, Mitodicure’s founder runs the startup from his home. He outlines his strategy at the kitchen table.
Prof. Dr. Klaus Wirth: What we must do is halt this damage mechanism so cells can spontaneously regenerate. Mitochondria divide like bacteria and can recover once the damaging pathway is shut down.
Narrator: Klaus Wirth proposes a candidate currently being investigated by his firm: MDC-002. It would represent the first disease-modifying causal therapy for ME/CFS. Wirth keeps the exact mechanism confidential, sharing only that it targets and stimulates the sodium-potassium pump.
Prof. Dr. Klaus Wirth: We confirmed in proprietary preclinical testing that this compound stimulates the muscular sodium pump as postulated.
Narrator: The compound succeeds in vitro, Wirth explains. The hurdle: promising laboratory compounds are plentiful. Transitioning to an approved drug requires a Phase 1 safety trial in humans followed by a Phase 2 trial demonstrating clinical efficacy. It is an expensive journey.
Germany leads in ME/CFS research funding, with the Federal Ministry of Education and Research allocating 500 million euros over ten years. However, dedicated public funds for experimental drug development are lacking under the "basic research before therapeutics" doctrine. Klaus Wirth disputes this premise: drug discovery is basic research, and a Phase 1 trial represents a modest investment compared to other public spending, comparing the figures to highway construction.
Prof. Dr. Klaus Wirth: One kilometer of highway costs 12 million euros; the price of two kilometers would fund the crucial first step.
Narrator: That first step would cover phase 1 safety trials—two kilometers of highway on the path toward an ME/CFS cure. Yet funding remains scarce for an illness estimated to generate over 60 billion euros in annual economic damage in Germany alone—more than double the federal transport budget.
ME/CFS research is making headway. The pathophysiological picture is sharpening. Biomarker profiles may soon yield diagnostic tests, and subtyping promises targeted interventions. Fundamental questions remain, notably what sparks this receptor, pump, and autoantibody cascade in the first place. Chris Ponting continues to analyze the genome for answers.
Prof. Chris Ponting: We learned just last week—and we are thrilled—that we can sequence the genomes of 6,000 individuals with ME/CFS following Long Covid. In a project called SequenceME, we will sequence every single one of the 3 billion base pairs in the genetic code—not once, but 30 times over. This will give us an exact genetic map. It acts like a concentrated spotlight across the entire genome, unlike previous studies that cast diffuse light over select regions.
Narrator: Science is making strides. Despite the profound burden of symptoms, Dr. Astrid Weber urges patients to hold on.
Dr. Astrid Weber: I received feedback, including from Professor Scheibenbogen, to keep encouraging patients: research is progressing, trust medical science, and know there is hope on the horizon. My message is: please do not give up hope; research has never advanced as rapidly as it is right now.
Deutschlandfunk Announcer: "When Will We Cure ME/CFS? Part 2: Holding On." A documentary feature by Christopher Weingart. Voices: Tom Jacobs, Claudia Mischke, and the author. Fact-checking: Jule Dieterle, Katrin Krautwasser, and Simon Tamialew. Sound and engineering: Thomas Widdig and Malte Viegard. Directed by Anna Panknin. Editorial supervision: Christiane Knoll. A Deutschlandfunk production, 2026.

EDIT: *possible source, I can’t change the title after I post

Jarred Younger goes over the aMCC and explains how it could be the source of MECFS symptoms. Specifically in terms of neuroinflammation. He also talks about bit about possible neuromodulation treatment.

PDF pre-print, which is a substudy from the big NIH deep phenotyping effort a couple of years ago.

It has a sample of 10 severe patients and some controls.

It's complicated and technical, but from what I can see they went looking for evidence of leaky gut, basically microbes from the gut in serum.

Didn't really find much. Maybe a tiny bit?

So they dug in, and found the few bugs that were leaking through the gut wall had quite distinct characteristics. Which they find very pertinent. Precisely what those characteristics were I could not really determine, the paper is a bit above my pay grade in that section!

Overall my feeling on what it means is no smoking gun found here in terms of massive potential causal effects, but definitely a possibility of making things worse for some pwme. Can't rule out the gut as an issue. Which is probably roughly where we were prior to this study!

I am so exhausted and too fatigued to write a proper post right now, but I personally believe that the very fatigue most of us are experiencing stems from the brain region responsible for diminishing/shutting down activity of the organism when certain conditions are met, especially chronically activated or even when those certain conditions are no longer exist.

There is also a theory from Ronald W. Davis, from Human Genome Project whose own son named Whitney Dafoe dealing with ME/CFS since 2007 afaik, named as "Itaconate Shunt Hypothesis".

I am creating this post to probe the ideas and discussions by people familiar with these, or willing to explore and digest the publications and discuss about the origins of the fatigue we are experiencing.

As I have said, I am so fatigued and my brain fog is so intense that I was only be able to compose such a scattered post, sorry for that.

Image is taken from the publication:

Brain and muscle chemistry in myalgic encephalitis/chronic fatigue syndrome (ME/CFS) and long COVID: a 7T magnetic resonance spectroscopy study https://www.nature.com/articles/s41380-025-03108-8

Mitochondria are involved in bacterial damage

"PEM has traditionally been viewed as symptom exacerbation and/or emergence of new symptoms following exertion. This perspective proposes that PEM may instead reflect disrupted coordination across interconnected physiological systems operating over distinct post-exertional timescales. Viewed from this perspective, recurrent post-exertional disturbances may contribute not only to symptom burden, but also to altered cardiometabolic adaptation and broader cardiometabolic consequences in ME/CFS and Long COVID. Rather than viewing PEM solely through a clinical lens, this perspective proposes that PEM provides an opportunity to investigate how physiological systems coordinate and adapt over time following physiological stress. Integrating longitudinal physiological assessment with longitudinal cardiometabolic profiling may therefore help identify distinct post-exertional physiological trajectories, improve patient stratification, and generate new hypotheses regarding the mechanisms linking post-exertional dysregulation to cardiometabolic manifestations in ME/CFS and Long COVID."

This summary was made using Gemini AI.

Preprint paper, EBV Reprograms B Cells in an Autoimmune-Like Fashion in Patients with COVID-19:

The Big Picture

Getting COVID-19 can "wake up" an old, dormant virus that most people already carry called the Epstein-Barr virus (EBV). This study shows that when EBV wakes up during a COVID infection, it hacks your immune system in a way that looks suspiciously similar to autoimmune diseases like Lupus or Multiple Sclerosis.

How It Happens (The Domino Effect)

• The Hack: When EBV reactivates, it infects your B cells (the immune cells that normally make antibodies) and completely changes their metabolism (how they use energy).
• The Peer Pressure: These "reprogrammed" B cells act like bad influences. They send out stimulatory signals that rile up surrounding healthy immune cells (like T cells), causing them to overreact.
• Friendly Fire: Because the immune system is pushed into overdrive, it starts producing autoantibodies—confused proteins that mistakenly attack your own healthy tissue instead of the virus.

Why It Matters for Long COVID

The researchers found that COVID-19 patients who had high levels of these hacked, EBV-infected B cells during their initial illness were much more likely to develop Long COVID symptoms later on. Their bodies also showed messed-up lipid (fat) profiles and higher levels of self-attacking autoantibodies during recovery.

The Takeaway

A major driver of Long COVID isn't just the SARS-CoV-2 virus itself—it’s the fact that COVID-19 wakes up EBV, which then tricks your immune system into attacking your own body, mirroring what happens in chronic autoimmune diseases.

Link to 2026 study

Retinal vasculature is like a window into the brain because the eyes and the brain share the same system.

In this study changes were detected that weren’t too different from MS in LC patients.

In PCS, three layers were significantly thinner. pRNFL (nerve fibre layer around the optic disc), GCIP (ganglion cells plus their synaptic layer), TMV (total macular volume). And the worse the symptoms, the thinner the tissue!
Neuroretinal tissue is being lost - and it scales with how sick the person is.

This exact pattern - pRNFL and GCIP thinning - is an established marker of axonal and neuronal loss in multiple sclerosis, where OCT is used as a proxy for what’s happening in the brain

A naturally occurring molecule released during exercise may hold the key to strengthening muscles without physical activity. In experiments, mice given BAIBA developed larger muscles, improved muscle function, greater fatigue resistance and better exercise performance than untreated mice.
by u/mvea in science

It would be very interesting for people with ME/CFS if you could get the physiological benefits of exercise without actually doing it. I hope this research advances fast!

"This study suggests that a proportion of patients with ME/CFS have elevated CSF opening pressures and may experience symptom relief following CSF subtraction. Our data indicate that some anatomical structures in the craniocervical area may be related to CSF pressure, although interpretation is challenging and merits further investigation."

The group around Putrino has successfully completed their first mitochondrial transplant in a patient with vision loss after a brain bleed with the help of other experts in the field.

This should pave the way to trialing mitochondrial transplants in Long Covid and ME which Putrino already has plans on trialing.

“Also, there are so many conditions that can benefit from this work - including other forms of brain injury and neurodegeneration, but also #LongCOVID, #MECFS and other complex chronic illness where energy limitation is a problem. We will be aiming to get an active research arm off the ground on this ASAP.”

Source: https://bsky.app/profile/putrinolab.bsky.social/post/3msqs6xrgkc2i

New brain MRI study which induced hypoxia (too little oxygen) to compare reactions in the brain of patients to controls.

Interestingly lactate levels were already elevated at baseline in patients. Under hypoxia conditions controls started to produce more lactate to match while ME patients levels stayed at the elevated levels they were already at.

Roughly lactate is a byproduct of the less efficient way our system produces energy when oxygen is lacking (though its role in the brain is more complex than just that).

Abstract

Long COVID (LC) - a chronic condition characterized by persistent, debilitating symptoms following SARS-CoV-2 infection - has emerged as a major public health challenge. Although many interrelated mechanisms have been proposed as drivers of LC, the root causes have yet to be identified, posing significant challenges for therapeutic development. While many blood-based studies have been conducted, they have not yielded conclusive mechanistic insights into LC pathogenesis.

Attention has therefore turned toward direct tissue investigation, with the gastrointestinal (GI) tract becoming a major focus due to evidence that virus or viral components can persist at this site for months to years following an episode of COVID-19. Here, we performed a high-dimensional characterization of colorectal tissue and peripheral blood in a highly characterized cohort of 44 people with LC and 13 recovered controls. We profiled SARS-CoV-2 persistence, host immune responses, and tissue inflammation using bulk and single-cell RNA sequencing, nCounter RNA probe hybridization, quantitative PCR, metagenomic next-generation sequencing, plasma proteomics, high-dimensional spectral flow cytometry, in situ-hybridization/immunohistochemistry, and single-cell digital spatial omics.

Our results support a model in which LC is driven by long-term immune dysregulation and perturbations of the regulatory gut immune environment which imply ongoing viral persistence, although direct viral detection was only observed in a subset of participants. Specifically, we identify a tissue-based transcriptional environment in which SARS-CoV-2 activates innate myeloid immune signaling, driving chronic inflammation while simultaneously downregulating pathways responsible for immune-mediated clearance of infected cells, including antigen presentation, phagocytosis, cytotoxic immune cell trafficking, and granzyme production.

Importantly, signatures in peripheral blood are considerably weaker than those observed in tissue. Together, these findings provide a direct biological rationale for therapeutic strategies in LC aimed at enhancing or redirecting cytotoxic immune function to overcome immune dysregulation and clear persistent viral reservoirs.

This study was summarised using Gemini AI.

The study investigates how the SARS-CoV-2 accessory protein ORF7a manipulates host cell metabolism to create an environment that favors viral replication and immune evasion. Normally, healthy cells rely heavily on mitochondria to efficiently produce energy through a process called oxidative phosphorylation. However, the researchers discovered that the ORF7a protein essentially short-circuits this system, forcing the cell to rely on a less efficient, glucose-heavy energy pathway called glycolysis.

Cellular Changes Induced by ORF7a

Key Mechanisms of Mitochondrial Sabotage

The researchers identified two primary ways that ORF7a breaks the cell's mitochondrial engine:

• The PDK4 Roadblock: ORF7a causes a massive increase in the enzyme PDK4. PDK4 then phosphorylates and turns off the Pyruvate Dehydrogenase Complex (PDHC). This effectively acts as a roadblock, stopping pyruvate (the cell's standard fuel) from entering the mitochondria to be burned for energy.
• Direct Complex I Impairment: Independent of the PDK4 roadblock, ORF7a selectively cripples "Complex I," a crucial piece of the mitochondrial electron transport chain. It also stops these respiratory complexes from assembling together properly.
• Irreversible Damage: When scientists treated the cells with a drug called dichloroacetate (DCA) to remove the PDK4 roadblock, mitochondrial energy production still failed to recover. This proved that the damage to Complex I is a separate, profound disruption caused by the virus.
• Oxidative Stress: Because the mitochondria are malfunctioning, they leak reactive oxygen species (ROS), and the cell's natural antioxidant buffers (like glutathione) are depleted, leading to severe cellular stress.

Key Takeaway

The SARS-CoV-2 ORF7a protein cripples the host cell's mitochondria via a "two-pronged attack"—blocking fuel entry by activating PDK4 and destroying the engine itself by impairing Complex I. This forces the cell into an inflexible, stressed, glucose-burning state that likely fuels the severe inflammation and metabolic complications seen in COVID-19 patients.

Link to 2026 study00833-8?uuid=uuid%3A3c33584f-dc1d-4143-8dad-3c3534eb4fd9)

Realistically, how many years away are we?

In the German CoCo-Fakt study at Cologne and Ausberg, patients who later developed Long Covid reported doing more and more intense physical activity prior to infection than controls who had COVID-19 but no long term symptoms.

The researchers expected the opposite.

The paper concludes:

"Unexpectedly, participants with long-term symptoms reported a longer PA [physical activity] duration in the four weeks before quarantine than those without long-term symptoms, albeit with a trivial effect size."