2025 brought big new clues about Long COVID and ME/CFS:

Genes tied to risk, immune and clotting changes, PEM findings, possible blood tests, and brain changes.

Here is an end of year round up in plain language. Long COVID genetics

A huge study of thousands of people found specific spots in our DNA that raise the risk of long COVID, many in immune and lung related genes. This confirms a clear biological driver.

New research shows major damage in the brain stress system of people with very severe ME/CFS.

The key finding: a near-loss of the neurons that start the cortisol stress response. This helps explain low cortisol and many symptoms.

Let’s break it down in simple language. Researchers studied brains from 7 people with ME/CFS who donated tissue after death.

They focused on the hypothalamus, a small brain region that controls energy, stress, and hormones.

Mild COVID in monkeys caused long lasting changes in brain and body.

Months later they still had problems with smell and taste, thinking, sleep and heart control.

This looks similar to long COVID in people. 10 adult rhesus macaques (5 female, 5 male) were infected with the early Wuhan strain. Illness was mild.

They were followed for 4 to 5 months with repeated tests.

Whole blood RNA sequencing can identify which high risk COVID 19 patients are most likely to worsen and which ones respond best to sotrovimab.

A similar method to what we aim to do in Long COVID and ME at @amaticahealth

Paper breakdown 🧵 @amaticahealth 302 trial participants had blood taken on day 1 and day 8.

RNA seq measured which genes were active. This data showed clear patterns that separated high and low risk patients.

Anktiva is probably one of the most interesting drugs in trial for Long COVID. It works by raising key immune cells that seem low or poorly functioning in LC condition.

This thread explains what the drug does and why researchers are testing it. Anktiva is a lab made version of a natural signal in the body called IL15.

IL15 tells certain immune cells to wake up, grow in number, and work more effectively. These cells include NK cells and CD8 T cells, which target infected or abnormal cells.

Extremely cool new study reports that people with Long COVID have higher levels of blood particles called extracellular vesicles (EVs). These particles also have more mannose, a type of sugar molecule.

This may allow a device called a GNA lectin filter to remove them. 🧵 EVs are tiny bubbles released by cells. They carry proteins and genetic material.

They can influence inflammation and the immune system. In Long COVID, EVs may help keep symptoms going.

New paper links EBV to Lupus.

In lupus (SLE), Epstein Barr virus (EBV) infects B cells that react to the body’s own nuclear material. EBV then changes these B cells so they act like antigen presenting cells. This may help drive the autoimmune process

Breakdown 🧵 EBV infects almost everyone, but only some people develop lupus. This study looked at how EBV behaves inside B cells in SLE compared to healthy people.

New research shows ME/CFS involves measurable DNA-level changes - including genetic risk factors, mitochondrial dysfunction, oxidative stress, and epigenetic reprogramming - linking it biologically to Long COVID and pointing to new diagnostic and treatment paths.

Let’s break it down🧵 Family and twin studies show ME/CFS is partly genetic. Identical twins share the illness much more often than non-identical ones, with heritability around 50%.

Genes, not just environment, strongly affect disease risk.

1/ New study tested blood from ME/CFS patients for 185 human viruses.

Result: healthy controls had more viral DNA than patients (Unexpected).

Only Varicella Zoster Virus (VZV) appeared more often in ME/CFS, hinting at possible reactivation in a subgroup.

Let’s break it down🧵 Researchers used a special molecular probe technology that searches for DNA from 185 known human viruses.

Each probe targets a short, unique sequence belonging to one specific virus.

New study on long COVID with ME/CFS looked at 78 patients and 62 recovered controls

Females - stronger inflammation, leaky gut, Treg loss, neuroinflammatory transcriptome, low testosterone

Males - persistent innate and interferon signaling, mitochondrial stress Methods in brief:

- Blood cell counts and flow cytometry

- Cytokine and chemokine panels

- Gut leak markers

- Sex hormones

- Whole-blood RNA sequencing

- Computational cell deconvolution (CIBERSORTx)

- Statistics and regression

New research has identified a potential biological cause for post-COVID fatigue/muscle fatigue.

Scientists found that a molecule called soluble IL-2 receptor (sIL-2R), linked to immune activation, may directly harm mitochondria in muscle cells. Two studies led by Brown et al. (a 2024 preprint and a 2025 peer-reviewed paper) examined blood and muscle samples from people with long-COVID fatigue compared to healthy controls.

Elevated Angiotensin II (AngII) in ME/CFS & Long COVID patients:

Ang II controls blood pressure and circulation. It can also affect insulin use in muscle, activate brain immune cells, and more.

Let’s breakdown the findings in simple terms 🧵 Ang II helps control blood pressure, circulation, and inflammation.

Too much Ang II can narrow blood vessels and increase stress inside the vascular system.

ROCK2 protein levels reduced in post-exertional malaise (PEM) ME/CFS and Long COVID cohort:

Patients who had blood drawn during PEM had significantly reduced ROCK2 than those who had blood drawn at baseline.

Preliminary finding. ROCK2 is an enzyme that helps control blood vessel tone, platelet function, and immune cell signaling.

It’s mainly inside cells, so changes in serum may be more complicated than simply just reduced protein levels.

🧵A new study analyzed blood from people with hypermobile Ehlers-Danlos syndrome (hEDS) and found strong evidence of immune dysfunction.

Complement proteins were consistently lower, cytokine signaling was altered, and structural collagen markers were normal. Researchers used mass-spectrometry and ELISA to compare 29 hEDS patients with 29 matched controls.

The results showed widespread immune and inflammatory changes, suggesting hEDS involves more than connective-tissue abnormalities.

🧵Super interesting new paper by @Jgburgess2 & Co: How IgG autoantibodies may cause fibromyalgia via mast cells.

Summary: IgG from fibromyalgia patients activates mast cells via the MRGPRX2 receptor, triggering inflammation & pain. Blocking this pathway could offer treatment. The researchers took IgG (an antibody type) from fibromyalgia (FMS) patients and injected it into mice.

The mice developed symptoms seen in human fibromyalgia: heightened pain from touch and cold, lower movement, and gut issues.

IgG from healthy people had no effect.

New interesting research POTS paper:

A large proportion of people with POTS - including those who developed it after COVID - have a measurable blood abnormality: a platelet storage pool deficiency.

Let’s breakdown what that means in simple terms.🧵 POTS (Postural Orthostatic Tachycardia Syndrome) is a condition where standing up leads to a large increase in heart rate, dizziness, fatigue, and other symptoms.

It’s now common in long COVID.

Up to 80% of long COVID patients may meet POTS criteria.

🧬 New finding from our @amaticahealth Long COVID & ME/CFS cohort:

We found elevated levels (P = 0.0351) of free TGF-β1 in Long COVID & ME/CFS serum samples.

This protein has been found elevated in multiple Long COVID & ME/CFS studies & may correlate with a subgroup. 🧵 TGF-β1 is a protein that regulates the immune system, tissue repair, and inflammation.

When free (active) TGF-β1 is elevated, it may affect how the immune system responds to infection, tissue injury, or chronic inflammation.

🧬 New finding:

Low serum ROCK1 levels have been identified in our Long COVID and ME/CFS @amaticahealth cohort.

ROCK1 is a regulatory protein involved in stress response, immune activity, and autophagy (cell recycling). Possibly having relevance in disease mechanisms. ROCK1 is a protein found inside cells. It helps regulate how cells move, contract, and respond to signals - including stress, inflammation, and damage.

It’s involved in multiple systems: immune, cardiovascular, neurological, and metabolic.

🔬❕We found reduced ACE protein levels in the blood of people with Long COVID & ME/CFS.

This could affect blood flow, fluid balance, inflammation, & brain function - potentially relevant to symptoms like orthostatic intolerance, brain fog, & chronic pain.

Let’s break it down. ACE (angiotensin-converting enzyme) plays a key role in blood pressure, fluid balance, and inflammation.

It converts angiotensin I to angiotensin II, and also breaks down bradykinin and substance P - both of which affect pain, blood vessels, and immune signaling.

🔬Most people think mast cells are only involved in allergies or rare conditions like MCAS or mastocytosis. That’s incorrect.

Research shows mast cells are active in many diseases, including neurodegenerative, autoimmune, infectious, heart, gut, and mental health conditions🧵 Mast cells sit in tissues like the skin, gut, and around blood vessels and nerves. When triggered, they release a large mix of chemicals: histamine, tryptase, chymase, cytokines (like TNF and IL-6), prostaglandins, and more.

These chemicals affect nearby cells and tissues.

🧵 T cell exhaustion - possibly one of the drivers of chronic infections in Long COVID & ME/CFS.

What is it, what genes are involved, and how we can gain insights with available testing.

Let’s break it down. 🧵 T cells are immune cells that normally help fight infections and cancer.

But when T cells are exposed to a threat for too long - like a virus or tumor that doesn’t go away - they can enter a state called “exhaustion.”