Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome, 2024, Saito

[Dolphin]

https://www.frontiersin.org/articles/10.3389/fimmu.2024.1341843/abstract

Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome

ORIGINAL RESEARCH article
Front. Immunol.
Sec. Viral Immunology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1341843
This article is part of the Research Topic
Cross-Reactive Immunity and COVID-19

Suguru Saito1 Shima Shahbaz1 Xian Luo1 Mohammed Osman1 Desiree Redmond1 Jan Willem Cohen Tervaert1 Liang Li1 Shokrollah Elahi1*

• 1University of Alberta, Canada

The final, formatted version of the article will be published soon.


A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease.

A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life.

A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed.

We identified and studied metabolites in LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).

Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups.

Plasma metabolomics analysis showed that LC differed from the R and HC groups.

Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma proinflammatory biomarkers (e.g. IL-1a, IL-6, TNF-a, Flt-1, and sCD14) but the reduction in ATP in LC patients.

Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease.

Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease.

Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting.

In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.

Therefore, our study findings provide a comprehensive metabolomic knowledge base for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients.

Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.



Keywords: Sarcosine, Serine, soluble CD14, Depression, Cognitive Performance

Received: 21 Nov 2023; Accepted: 04 Jan 2024.

https://twitter.com/user/status/1745553170657316889

 

[SNT Gatchaman]

Now published.

 

[Solstice]

Those markers look really familiar from somewhere.

 

[SNT Gatchaman]

However, the levels of other metabolites such as 5-Aminolevulinate, cysteate, putrescine, 4-Aminobutyraldehyde, kynurenine, serotonin, Formyl-5hydroxykynurenamine, 5-Hydroxykynurenine, 2-Aminomuconate, xanthine, and 5-Aminolevulinate were significantly increased in LC patients

 

[Dolphin]

Press release for this Canadian study [Metabolomic and immune alterations in #longCOVID patients with #ChronicFatigueSyndrome]:
https://www.ualberta.ca/folio/2024/...ly-identical-to-chronic-fatigue-syndrome.html

https://twitter.com/user/status/1755756895455903799

“We do not actually believe that #longCOVID is a separate new disease,” explains rheumatologist and clinical immunologist Jan Willem Cohen Tervaert, professor of medicine, who is an expert in fatigue associated with rheumatic illnesses. (contd)"

(Contd) “Some symptoms — such as the loss of taste and chest pain — are very specific for #COVID, but we see a common pathway with ME/CFS, which leads to the same fatigue, brain fog, post-exertional malaise, widespread pain and non-refreshing sleep,” he says. #MEcfs #CFS #PwME

https://twitter.com/user/status/1755757967243096402

https://twitter.com/user/status/1755758778505396612

 

[forestglip]

This is on patients who have long COVID and ME/CFS. ME/CFS diagnosis seems to be based on the DePaul symptom questionnaire. I'm not sure if they also had to fulfill other criteria.

A key strength of this study was our unique focus on LC patients who met classification criteria for ME/CFS, which was not rigorously performed in any previous study. Those LC patients who did not fulfill ME/CFS criteria were excluded.

Our LC patients were evaluated based on diagnostic criteria developed by CDC and WHO (30, 31) for ME/CFS. Moreover, we used a set of validated clinical questionnaires to capture the severity of symptoms for ME/CFS.

The diagnosis of ME/CFS was made if the patients met the criteria for categories I, II, III, IV, V, and VI (32–34). [of the DSQ]

Strikingly large difference between groups for anti-calcium sensing receptor (CaSR) antibodies:

In light of hypocalcemia in COVID-19 patients and its association with hypoparathyroidism (39, 40), we detected significant levels of the anti-CaSR antibody (calcium receptor) in LC cohort (Figure 6K).

No difference for levels of CaSR itself:

This observation forced us to measure the soluble form of CaSR in our different cohorts. Interestingly, we observed the elevation of soluble/shed CaSR in the plasma of acute COVID-19 patients, which was not the case in LC patients

 

[ScoutB]

Really interesting.

I vaguely remember a study not too long ago looking broadly at antibodies in either ME/CFS or LC. I think they might've run blood through some kind of large standard array that tests for many different kinds of antibodies at once? Can't even remember if it was just auto-antibodies or viral or something. Can't find it now of course.

I don't really have a sense for how thoroughly we've searched for antibodies. So when something like this comes up I wonder if it's an example of something we wouldn't have found before because we didn't know to look for it, or this result kind of contradicts other antibody studies that found minimal differences.

 

[V.R.T.]

Strikingly large difference between groups for anti-calcium sensing receptor (CaSR) antibodies:

There's been some discussion about calcium on here recently iirc, I think in the context of Type 1 interferons and mtDNA and all that but I could be misremembering.

 

[V.R.T.]

This is on patients who have long COVID and ME/CFS. ME/CFS diagnosis seems to be based on the DePaul symptom questionnaire. I'm not sure if they also had to fulfill other criteria.




Strikingly large difference between groups for anti-calcium sensing receptor (CaSR) antibodies:

View attachment 32033

No difference for levels of CaSR itself:

View attachment 32034

Found a few from a quick search:

An emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis

Mathavarajah, Sabateeshan; Salsman, Jayme; Dellaire, Graham

Abstract
Type I interferons are effector cytokines essential for the regulation of the innate immunity. A key effector of the type I interferon response that is dysregulated in autoimmunity and cancer is the cGAS-STING signalling axis.

Recent work suggests that calcium and associated signalling proteins can regulate both cGAS-STING and autoimmunity. How calcium regulates STING activation is complex and involves both stimulatory and inhibitory mechanisms.

One of these is calmodulin-mediated signalling that is necessary for STING activation. The alterations in calcium flux that occur during STING activation can also regulate autophagy, which in turn plays a role in innate immunity through the clearance of intracellular pathogens. Also connected to calcium signalling pathways is the cGAS inhibitor TREX1, a cytoplasmic exonuclease linked to several autoimmune diseases including systemic lupus erythematosus (SLE).

In this review, we summarize these and other findings that indicate a regulatory role for calcium signalling in innate and autoimmunity through the cGAS-STING pathway.

Web | DOI | Cytokine & Growth Factor Reviews

Something I only recently got my head around is what CD38 is. Posting in case it helps others and to check my understanding if anyone wants to correct me!

I assumed a straight receptor. Then found it had dual (or multiple) roles but I was still thinking about it wrong. Now I may still be wrong but by understanding is it’s a cell surface protein and it can be utilised as an enzyme in certain processes (like creation of cADPR which is important for calcium signalling) or act as a receptor (like binding to CD31 on T cells which triggers cytokine production as mentioned here).

So when daratumumab acts upoon it, depending on what cell and what role it can have different effects. It may start a process which kills the cell, or it may reduce availability an enzyme the cell needs for calcium signalling, or, I guess other things?

And can’t IFN increase CD38 too?

 

[V.R.T.]

Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels

Spoiler: Authors

DeMeulenaere, Kaitlyn E.; Grant, Rogan A.; Martin, Megan E.; Valencia, Hiam A.; Radulovic, Jelena; Salter, Michael W.; Prakriya, Murali

Abstract
Microglia are the brain’s resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca 2+ signaling in regulating broader microglial cell state transitions and identified Orai1 Ca 2+ channels as critical regulators of microglial plasticity and neuroinflammatory signaling. Conditional deletion of Orai1 in microglia impaired their ability to adopt reactive, proinflammatory states.

Transcriptomic and metabolomic profiling revealed that Orai1 deletion suppressed the expression of proinflammatory genes linked to immunity, inflammation, and cell metabolism. Conversely, Orai1-deficient microglia generated greater amounts of neuroprotective and anti-inflammatory mediators, including BDNF, ARG1, and the mitochondrial metabolite itaconate. In a model of CNS inflammation induced by peripheral lipopolysaccharide (LPS) challenge, microglial Orai1 deletion attenuated microglial and astrocyte reactivity and reduced hippocampal amounts of the proinflammatory cytokines IL-1β and IL-6.

Consistent with these cellular changes, microglial Orai1 knockout mice were protected against LPS-induced decreases in motivational behaviors, including impaired reward-seeking and escape behaviors. These findings establish Orai1 channels as key regulators of microglial cell state transitions, linking Ca 2+ signaling to neuroinflammation and inflammation-driven behavioral dysfunction.

[Paragraph breaks added]

Web | DOI | Science Signaling