Thread by @tessfalor

#IIMEC15 Dr Bhupesh Prusty @BhupeshPrusty

Herpesvirus reactivation as a trigger for
mitochondrial dysfunction in ME/CFS

Hypothesis: acute vs chronic contributors to #MECFS

Normally look into peripheral circulation, but it's connected with tissue

some patients have MCAS, connective tissue issues, microclots

think disease starts in brain, astrocytes, glial cells, muscle cells

Unifying hypothesis - post viral illness, viral reactivation

when we look peripherally, don't find it

Many of symptoms belong to the chronic phase, after a couple months

In acute phase innate immune response fights it off, (in that phase neuronal and ANS abnormalities)

Study population

healthy controls N=83
#MECFS N=106
No LC N=149
Mild LC N=107
Severe LC N=23

LC = 6-12 months after SARS-CoV-2 positive

Herpesvirus signature in #MECFS and #LongCovid -
looked at specific herpesvirus dUTPase proteins. Expressed very early, "leaky virus reactivation"

developed test themselves

in LC HSV-1 reactivation in more than 50% of severe
#LongCovid

There is frequent herpesvirus reactivation in #MECFS and #LC

HYPERfusion of mitochondria (not fragmentation)

mitofusin 1 upregulated, autophagy inhibited

Prolonged virus infection and autoimmunity

autoimmunity expected to play a role in #MECFS

some say GPCR antibodies high in these patients

If there is autoimmunity playing a role, can we divide group based on what autoantibody?

Looked into 120 different IgG and IgM in different types of autoimmune and 120 different pathogen IgG and IgM

IgG response didn't divide patients. Random

IgM separated into 3 different groups (severe, control, and mild #MECFS)

antibody against CRP very high in #MECFS

IgM response against fibronectin depleted in severe ME

IgM against pathogen-associated antigens

majority of ME/CFS have increased IgM against a lot of environmental antigens

IgM against aquaporin-4 in optic nerves - matched with light sensitivity

circulating immunoglobulins and mitochondrial health

put IgG from severe into healthy cells in culture, in human endothelial cells - causes strong mitochondrial fragmentation (mitofusin 1 down)

What is in the immune complex?

depleted in ME/CFS - TF, A2M, Fibronectin 1 (FN1)

#MECFS higher serum fibronectin & correlates with disease severity

in #longCOVID also trend with severity

gender based differences in serum fibronectin

female usually have more fibronectin, so might reach pathological level easier

Study of trypanosoma infection - fibronectin went up and IgM-FN went down, after 3 wakes when started to recover FN goes down and IgM-FN goes up

FN is used by borrelia for tissue colonization

FN helps in HIV infection and many other viral infections

IgM against fibronectin is NATURAL IgM

produced by itself, doesn't require an antigen

Review paper: the importance of natural IgM: scavenger, protector and regulator

autoimmunity is associated with losing natural IgM, start developing autoimmunity against dying cells in body.

depletion of natural IgM against fibronectin is found in ME/CFS and Long COVID

Is it just one IgM, or total IgM in the body?

natural IgM-PC and MDA decreased in #LongCovid

in #MECFS severe patients also have low amount of the natural IgMs

How much does #MECFS and #LongCOVID overlap?

ME and LC, similar, but slightly more in LC (except vs severe ME)

When HSV-6 reactivates, it suppresses SARS-CoV2

looking at #longCOVID converting into #MECFS

looked at 3 people 18-24 months post SARS-CoV2 infection

Can see much lower IgM against fibronectin in LC cases that converted to ME/CFS

Summary of hypothesis: #MECFS starts with viral infection, leads to mitochondrial dysfunction in localized cell

viral activation reaches lymphoid tissue (didn't quite hear this part) - showed bone marrow, spleen, MALT

depletion of natural IgM
chronic inflammation, increased… twitter.com/i/web/status/1…