Interesting analysis. Thank you.
(If the Comey case reaches the Supreme Court, this could give SCOTUS a basis for rolling back unfettered presidential immunity … which they probably regret they ever ‘gave’ him in their earlier determination).
Different HLAs? So you're arguing that the reinfected RI group comprises people with less protective HLA alleles ie B*46:01, C*01:02?
If true this alone would be cause for concern, that a significant population is prone to repeated infection (and concomitant persistent multi-organ dysfunction).
Yep. I’m surprised you’re not familiar with them. The most variable part of the TCR and underlies broad protective T-cell immunity
SARS-CoV-2-specific CDR3α & CDR3β amino acid sequences from the VDJdb database (a curated repository of experimentally validated T-cell receptor-antigen interactions)
HC = protective T-cell repertoire
RI is missing many SARS-CoV-2-specific TCR V(D)J combinations (cf HC) that SHOULD exist (both HC & RI infected in China’s first wave in December 2022 wave)
RI is missing many SARS-CoV-2-specific CDR3 motifs.
➝ RI is not retaining broad, protective T-cell memory
Yes, those reinfected (RI):
▷ have fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
▷ lack protective CDR3 motifs: RI=3070 vs HC=3321
Their T-cell landscape fails to retain broad, protective T-cell memory
This isn’t “normal” ❌
The reinfected RI group
* share fewer SARS-CoV-2-specific TCR V(D)J combinations
- VJ: RI=44,919 vs HC=57,399
- VDJ: RI=11,902 vs HC=18,128
* lack protective CDR3 motifs: RI=3070 vs HC=3321
Their TCR landscape is a failure to retain broad, protective T-cell memory
This isn’t “normal” ❌
2/2
Thank you, I take your point, there’s no sign of persistent dysfunction in the healthy convalescent (HC) group at 9 months (T-cells have adapted appropriately). ✅
BUT in the reinfected RI group T-cell memory failed to mature into the HC protective state. That’s the issue.
1/2
Unfortunately, I don’t think you know what you are talking about. Even Prof Veldhoen sees an effect, but he argues this is a natural “learning” by the immune system. The debate is around whether SC2 in addition narrows immune flexibility and therefore response to novel pathogens.
… in determining V(D)J bias the Frontiers authors explicitly note that “reference repertoires from healthy donors” were used for baseline comparison. These are drawn from public pre-pandemic databases of uninfected individuals (not their own cohort).
There’s your healthy ‘controls’ for comparison.
‘Biased’ V(D)J usage is by definition wrt a naive (uninfected) population. The HC group at 9 months showed skewed V(D)J usage. By definition this reduces diversity in the TCR repertoire … some patterns will be missing, unavailable for recognition & clonal expansion
cf a naive (not infected) group.
By definition in non-infected groups there is no V(D)J segment bias (by definition) … but we see this in the Healthy Convalescent HC group at >9 months.
The HC group is measured at >9 months from infection. Hence, persistent skewing [V(D)J segment bias, especially TRAV35/TRAJ42].
Show me a reference for another disease that you:
(a) get once every 1-2 years (at least) and (b) has the same impact on T cells.
Healthy Convalescents (HC) were analysed 9 months post infection and showed clear V(D)J segment bias, especially TRAV35/TRAJ42, indicating persistent (>9 months) repertoire skewing (non-infected people would not show this skewing).
Yes, there is another infection where there is loss of TCR diversity (severe & progressive) and skewed V(D)J usage (persistent): HIV ➝ AIDS
So you are right, similar effects are seen in another infectious disease: HIV/AIDS
2/2 After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent remodelling.
1/2
After 9 months the TCR diversity in HC (convalescent) group is higher than in acute infection (some recovery), but LOWER than uninfected controls and also skewed, with biased V(D)J usage.
This is not a “naive-like” repertoire … after (at least) 9 months = persistent.
The immune system’s available T-cell pool is reallocated, inappropriately skewed toward antigenic specificities.
Persistent remodelling will inevitably carry a functional cost (even if not yet directly demonstrated) by narrowing the diversity of T-cells available to respond to unfamiliar pathogens.
Dysfunction ≠ lymphopenia
Frontiers doesn’t claim that SARS-CoV-2 kills T-cells or causes lymphopenia. It finds significant skewing in TCR repertoire diversity after recovery & reinfection that is unusually *persistent* for an acute infection
reducing flexibility to respond to novel pathogens.
This is the most important paper to demonstrate the endless capacity of COVID to stuff your immune system.
The #Leonardi_Effect is real 🙏🏻
www.frontiersin.org/journals/imm...
So this is a cumulative immune remodelling (not “nothing to see here”) and a progressive narrowing of adaptive options with fewer unique TCRs to meet the next novel pathogen.
Repeated COVID infections leave us less equipped to deal with novel pathogens.
That’s WHY we’re getting sicker more often.
WRONG
You:
1) Confuse transient repertoire contraction with normal clonal expansion
2) Wrongly assume no lymphopenia = no immunological dysfunction
3) Claim the Frontiers paper shows normal memory formation. No, it is evidence of cumulative immune remodelling (persistent, skewed changes)
etc
ie 3) There’s persistent changes in TCR repertoire diversity after reinfection. T-cell memory responses differ qualitatively (biased VDJ usage, distinct clonotypes) suggesting functional reshaping of the T-cell pool after repeated SC2 infections
That is not “no effect”. It’s cumulative remodelling.
i.e.
2) Absence of gross lymphopenia does not rule out phenotypic exhaustion, altered subset ratios, or defective proliferative potential. The Frontiers data (especially TCRβ diversity and CDR3 usage) suggest selective repertoire narrowing, even without overall cell loss.
i.e.
1) Frontiers measured persistent repertoire constriction and altered TCR usage patterns after reinfection, not the benign, transient effect you claim
WRONG
You:
1) Confuse transient repertoire contraction with normal clonal expansion
2) Wrongly assume no lymphopenia = no immunological dysfunction
3) Claim the Frontiers paper shows normal memory formation. No, it is evidence of cumulative immune remodelling (persistent, skewed changes)
etc
Duckworth: "He's accepting a bribe, which is unconstitutional and illegal. And he's gonna accept an aircraft that then is gonna cost taxpayers another billion dollars at a time when he wants to cut funding for Medicaid. It's simple unacceptable."
A photo of selling your soul for ambition.
Yeah, totally consistent.
