Long COVID involves activation of proinflammatory and immune exhaustion pathways, 2025, Aid et al.

Chandelier

Chandelier

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Long COVID involves activation of proinflammatory and immune exhaustion pathways

Aid, Malika; Boero-Teyssier, Valentin; McMahan, Katherine; Dong, Rammy; Doyle, Michael; Belabbaci, Nazim; Borducchi, Erica; Collier, Ai-ris Y.; Mullington, Janet; Barouch, Dan H.

Abstract​

Long COVID (LC) involves a spectrum of chronic symptoms after acute severe acute respiratory syndrome coronavirus 2 infection.
Current hypotheses for the pathogenesis of LC include persistent virus, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction and complement activation.

We performed immunological, virological, transcriptomic and proteomic analyses from a cohort of 142 individuals between 2020 and 2021, including uninfected controls (n = 35), acutely infected individuals (n = 54), convalescent controls (n = 24) and patients with LC (n = 28).
The LC group was characterized by persistent immune activation and proinflammatory responses for more than 180 days after initial infection compared with convalescent controls, including upregulation of JAK-STAT, interleukin-6, complement, metabolism and T cell exhaustion pathways.
Similar findings were observed in a second cohort enrolled between 2023 and 2024, including convalescent controls (n = 20) and patients with LC (n = 18).

These data suggest that LC is characterized by persistent activation of chronic inflammatory pathways, suggesting new therapeutic targets and potential biomarkers of disease.

Web | DOI | PDF | Nature Immunology
 
Jonathan Edwards said:
No data given, just interpretation.
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They have quite a lot of graphs and charts in the article - what they claim to have found would fit with a lot of what we discuss here.

They claim to have found an increase in IFN-Y and IFN a/b, along with JAK 3 and complement c2 and c4, and they say:
IFNγ, IL-6, JAK-STAT and T cell exhaustion pathways correlated with clinical symptoms in the group with LC, including fatigue, shortness of breath and cognitive complaints (Fig. 2e).
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IL-6 has been coming up a lot lately...
 
V.R.T. said:
What do people actually mean when they say T Cell exhaustion?
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I have several emails in my inbox from immunologists complaining about inappropriate use of the term, funnily enough.

In my opinion the only remotely coherent definition for "T cell exhaustion" is in specific contexts like cancers and chronic infections in tissue. What it means is that when you sort T cells that specifically recognize an antigen and stimulate them with that same antigen, they produce a much lower level of cytokines/effector molecules compared to appropriate controls. This phenomenon has been decently associated with poorer outcomes in those specific contexts--likely due to impaired ability of T cells to kill infected or cancerous cells and control spread over time.

That impaired effector function was found to correlate with certain metabolic changes and expression of certain markers like PD-1 in the T cells, so that became known as an "exhaustion signature." It's only ever a small subset of T cells that show those changes and often its only observable in T cells collected from the specific microenvironment harboring the infection or tumor. We don't know exactly why it happens, but the best evidence we have indicates that it's probably a combination of local signaling from other cells at the site of infection/cancer and repeated TCR stimulation leading to transcriptional changes in the T cells.

But the term "exhaustion" constantly gets brought up outside of that very specific context, so people will claim "T cell exhaustion" based on total quantification of some of those cytokines or expression of markers like PD-1 without sorting for antigen-specific T cells. Those differences in cytokines may be real, but you really can't infer anything about T cells or pathogens from them. It's the same logic as surveying how many times any fire alarm goes off in two large apartment complexes, finding that the frequency is lower in one of them, and then blaming the difference on every (or some unspecified subset) of fire alarms in the building being faulty. 99% of mentions of "exhaution" in LC or ME/CFS research are in this category.
 
jnmaciuch said:
I have several emails in my inbox from immunologists complaining about inappropriate use of the term, funnily enough.

In my opinion the only remotely coherent definition for "T cell exhaustion" is in specific contexts like cancers and chronic infections in tissue. What it means is that when you sort T cells that specifically recognize an antigen and stimulate them with that same antigen, they produce a much lower level of cytokines/effector molecules compared to appropriate controls. This phenomenon has been decently associated with poorer outcomes in those specific contexts--likely due to impaired ability of T cells to kill infected or cancerous cells and control spread over time.

That impaired effector function was found to correlate with certain metabolic changes and expression of certain markers like PD-1 in the T cells, so that became known as an "exhaustion signature." It's only ever a small subset of T cells that show those changes and often its only observable in T cells collected from the specific microenvironment harboring the infection or tumor. We don't know exactly why it happens, but the best evidence we have indicates that it's probably a combination of local signaling from other cells at the site of infection/cancer and repeated TCR stimulation leading to transcriptional changes in the T cells.

But the term "exhaustion" constantly gets brought up outside of that very specific context, so people will claim "T cell exhaustion" based on total quantification of some of those cytokines or expression of markers like PD-1 without sorting for antigen-specific T cells. Those differences in cytokines may be real, but you really can't infer anything about T cells or pathogens from them. It's the same logic as surveying how many times any fire alarm goes off in two large apartment complexes, finding that the frequency is lower in one of them, and then blaming the difference on every (or some unspecified subset) of fire alarms in the building being faulty. 99% of mentions of "exhaution" in LC or ME/CFS research are in this category.
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Thank you, a very helpful response!
 
jnmaciuch said:
I have several emails in my inbox from immunologists complaining about inappropriate use of the term, funnily enough.

In my opinion the only remotely coherent definition for "T cell exhaustion" is in specific contexts like cancers and chronic infections in tissue. What it means is that when you sort T cells that specifically recognize an antigen and stimulate them with that same antigen, they produce a much lower level of cytokines/effector molecules compared to appropriate controls. This phenomenon has been decently associated with poorer outcomes in those specific contexts--likely due to impaired ability of T cells to kill infected or cancerous cells and control spread over time.

That impaired effector function was found to correlate with certain metabolic changes and expression of certain markers like PD-1 in the T cells, so that became known as an "exhaustion signature." It's only ever a small subset of T cells that show those changes and often its only observable in T cells collected from the specific microenvironment harboring the infection or tumor. We don't know exactly why it happens, but the best evidence we have indicates that it's probably a combination of local signaling from other cells at the site of infection/cancer and repeated TCR stimulation leading to transcriptional changes in the T cells.

But the term "exhaustion" constantly gets brought up outside of that very specific context, so people will claim "T cell exhaustion" based on total quantification of some of those cytokines or expression of markers like PD-1 without sorting for antigen-specific T cells. Those differences in cytokines may be real, but you really can't infer anything about T cells or pathogens from them. It's the same logic as surveying how many times any fire alarm goes off in two large apartment complexes, finding that the frequency is lower in one of them, and then blaming the difference on every (or some unspecified subset) of fire alarms in the building being faulty. 99% of mentions of "exhaution" in LC or ME/CFS research are in this category.
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I second @V.R.T. — that response is a home-run explanation. Thank you, @jnmaciuch

I've also had multiple back-and-forths with one particularly prickly immunologist who was obstinate in his refusal to expand on why any mention of immune exhaustion was (in his words) "alarmist misinformation". His go-to was always arguing from authority: "Leave it to the experts" (as if we'd solved Post Acute Infection Syndrome, which he had no interest in discussing — thanks for nothing, Marc Veldhoen).

I actually went so far as to ask r/immunology this week for leads on respected immunologists in a bid to break from the whole "COVID is nothing" vs "COVID is AIDS" false dichotomy. (In both cases, an oversimplication of a complex and still misunderstood disease).

Given that this study is under the aegis of Dan Barouch, an Oxford graduate in immunology with an M.D. from Harvard Medical School (as well as being the director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center), one would think their use of "immune exhaustion" might actually be valid. (One of Veldhoen's go-tos is always "none of the researchers are even immunologists" — well, they are this time, buddy boy). I haven't looked at the nitty gritty and don't have the requisite training to correctly assess it.

What I do know, however, is that this field of medicine remains very much in flux and that dogma is no friend to scientific investigation. My hope is that these findings might eventually expand our understanding as to WTF is wrong with me—I mean, us.
 
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Covidivici said:
Given that this study is under the aegis of Dan Barouch, an Oxford graduate in immunology with an M.D. from Harvard Medical School (as well as being the director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center), one would think their use of "immune exhaustion" might actually be valid.
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Unfortunately not, they only assessed genes/proteins that commonly change in those specific “exhaustion” contexts I mentioned. The signature was significantly differential but we can’t infer what it means.

I know plenty of well-trained immunologists who use the term willy nilly, and plenty of equally impressive immunologists who chastise them for it. Sometimes endlessly on email threads I’m CC’d on.
 
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jnmaciuch said:
Unfortunately not, they only assessed genes/proteins that commonly change in those specific “exhaustion” contexts I mentioned. The signature was significantly differential but we can’t infer what it means.

I know plenty of well-trained immunologists who use the term willy nilly, and plenty of equally impressive immunologists who chastise them for it. Sometimes endlessly on email threads I’m CC’d on.
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Beyond the immune exhaustion terminology misuse debacle, what is your read on this paper? They claim to have found some interesting stuff but I'm not qualified to assess whether they really have.
 
jnmaciuch said:
Unfortunately not, they only assessed genes/proteins that commonly change in those specific “exhaustion” contexts I mentioned. The signature was significantly differential but we can’t infer what it means.

I know plenty of well-trained immunologists who use the term willy nilly, and plenty of equally impressive immunologists who chastise them for it. Sometimes endlessly on email threads I’m CC’d on.
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Dammit.
But as the husband of an up-do-date ER physician, that very much checks out. I'm constantly taken aback at little intellectual rigour (formerly) overachieving people apply on a daily basis. The stories I hear.......
 
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I will also note—they did check [edit: IFN-g response of T cells to spike protein stimulation] (Fig 1). And, exactly the opposite from what you’d expect in an “exhausted” T cell, IFN-g production was higher in LC.

[Edit: so the specific T cell response to COVID does not appear to be blunted in LC, even if some of the genes associated with “exhaustion” are higher when you measure all PBMCs together. This means that whatever is happening in the T cells of LC, it’s not antigen-specific “exhaustion”]
 
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V.R.T. said:
Beyond the immune exhaustion terminology misuse debacle, what is your read on this paper? They claim to have found some interesting stuff but I'm not qualified to assess whether they really have.
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it’s pretty much the exact same type of study as a paper I co-authored https://www.s4me.info/threads/ident...-2025-gabernet-et-al.42638/page-2#post-640199

Just way smaller cohort and much more limited in what they assessed. Some of the signatures here did come up in our analysis (like IL-6), but the association was weaker and did not pass our feature selection thresholds so we could not highlight them. This study was very much designed with the intention of finding immune signatures—our study was capable of finding the same pathways, but other pathways ended up providing a much stronger signature and overshadowed the few theyre highlighting here.

I’d need more time to dig into the methods to judge how rigorous this was. I’m obviously going to be biased trusting my team’s methods and findings over these where they diverge
 
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Now that I’ve had a chance to look through the methods, it looks fine to me. The analysis uses appropriate tools and statistical tests as far as I can tell.

I would have liked to see a multi-omic integration method of their cytokine data, transcriptomics, and proteomics to facilitate feature selection. The way they use it here is basically validating signatures from one assay in another, which is a fine alternative, it just means the analysis is less unbiased discovery and more seeking specific evidence to confirm a general hypothesis of “immune dysregulation.”

The main takeaway is just that these associations are on the weaker side. The way they present the data as logFC/z scores and pathway NES is somewhat standard in the field but can serve to make weak findings look more impressive than they are. All in all it’s one more study showing slight differences in immune signaling pathways in LC, some of which have come up repeatedly between studies and many of which do not replicate. The usefulness mostly comes down to how stringently they defined LC, which I don’t see much information on in the methods and don’t have time to chase down.
 
V.R.T. said:
Which pathways/signals are you referring to here?
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From this paper, IL-6 and JAK-STAT. From other papers, heme metabolism and platelet coagulation. Specific to LC studies, not ME/CFS more broadly (if I’m remembering correctly). If any of those signals are real they are on the weaker side—all usually found in screens of blood cells or plasma proteins/metabolites, too, because blood is the easiest to study. But you might only be seeing weak echoes of the real problem in blood.
 
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