Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination

nerd

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This article is a preprint and has not been peer-reviewed.

Lavanya Visvabharathy, Barbara Hanson, Zachary Orban, Patrick H. Lim, Nicole Palacio, Rishi Jain, Eric Michael Liotta, Pablo Penaloza-MacMaster, Igor J. Koralnik
medRxiv 2021.08.08.21261763
doi: 10.1101/2021.08.08.21261763

Summary
The high prevalence of post-acute sequelae of SARS-CoV-2 infection (PASC) is a significant health concern. In particular, virus-specific immunity in patients who suffer from chronic neurologic symptoms after mild acute COVID remain poorly understood. Here, we report that neuro-PASC patients have a specific signature composed of humoral and cellular immune responses that are biased towards different structural proteins compared to healthy COVID convalescents. Interestingly, the severity of cognitive deficits or quality of life markers in neuro-PASC patients are associated with reduced effector molecule expressionn in memory T cells. Furthermore, we demonstrate that T cell responses to SARS-CoV-2 mRNA vaccines are aberrantly elevated in longitudinally sampled neuro-PASC patients compared with healthy COVID convalescents. These data provide a framework for the rational design of diagnostics and predictive biomarkers for long-COVID disease, as well as a blueprint for improved therapeutics.
 

Pyrrhus

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Thanks so much, @nerd, for posting this!


Here, we report that neuro-PASC patients have a specific signature composed of humoral and cellular immune responses that are biased towards different structural proteins compared to healthy COVID convalescents.
Towards a potential biomarker for Long Covid? (or simply déjà vu for ME?)


Furthermore, we demonstrate that T cell responses to SARS-CoV-2 mRNA vaccines are aberrantly elevated in longitudinally sampled neuro-PASC patients compared with healthy COVID convalescents.
Could this provide more support for the idea that Long Covid patients are more likely than "healthy COVID convalescents" to have impaired production of antibodies, with compensatory T cell responses?
 

nerd

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Towards a potential biomarker for Long Covid? (or simply déjà vu for ME?)
In particular, N protein-specific vs. M protein-specific CD134+ CD137+ CD4+ Tfh cells could be. This seems to be the biomarker with the greatest difference among groups.

Could this provide more support for the idea that Long Covid patients are more likely than "healthy COVID convalescents" to have impaired production of antibodies, with compensatory T cell responses?
There's clearly a difference in antigen stimulation from N vs. M protein by this subset of CD4+ T follicular helper cells. IgGs responses also differ towards these two virus protein types.

CD8+ TEM were significantly activated by various S, N, and M peptide pools in CC subjects while remaining relatively quiescent after antigen stimulation in CN patients (Fig. 4A-B).
T effector memory cells didn't respond to antigens as well in Neuro-PASC patients.

Total percentages of CD8+ TEMRA cells were significantly elevated in CN compared with CC and HC groups (Fig. 4C), but despite their increased numbers, CD8+ TEMRA cells were less activated by the S3/4 peptide pool in CN patients and showed a trend towards decreased activation after N pool stimulation compared with CC subjects (Fig. 4D-E).
It's difficult to make sense of this. There are more accumulated CD8+ TEMRA cells in Neuro-PASC patients but with less activation. This is an indicator that these patients might have been preexposed to chronic infections, impairing a proper CD8+ cytotoxic response to the S and N proteins. It's possible that this is just a correlating factor that shows us a predisposition of the affected patients. It's also possible that this also plays a role in the pathophysiology because the impaired immune response against spike proteins will have consequences.

Perhaps, CD4+ T follicular helper cells have to compensate for this by pushing adaptive immunity to its limits. Or maybe, there is a dysfunctional antigen presentation and this is the reason for these discrepancies in the CD4+ Tfh activation. Somehow, IFN-gamma from these Tfhs also doesn't correlate with IgG activation, not that I can clearly see it in the charts though.

I think it's also consistent with the hypothesis that SARS-CoV-2 remains dormant in cells. Without a good immune response against spike proteins, more cell fusion can happen. This means that there will be more N proteins in circulation. The lower M protein-specific CD4+ Tfh activation might be either because N proteins constitute more proteins overall than membrane proteins, or because N proteins are the remainder of SARS-CoV-2 inside cells.

Or maybe I'm seeing it from the wrong perspective. Maybe the M proteins M1 and M2 where the IL-2 response is only poor contribute to some kind of pathology and the consequence is more N proteins in circulation. Because in the measured cytokine response from N proteins, there wasn't any outstanding subtype of the protein.

One more thought. The lack of cytotoxic response also affects these proteins differently and how they can be processed as antigens. I assume that N proteins are more frequent inside of cells than outside when compared to the other proteins. Maybe their only issue was chronic subclinical infection from another virus and the lack of cytotoxic response did the rest.