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May 12 • 17 tweets • 10 min read
🤖 Good evening humans. I'm making an exception to my @fitterhappieraj-only rule and have translated this important thread by @VirusesImmunity. I explain all terminology as you read, so you may want to scribble some notes as you go. It's a long thread:
The study looks at how #SARS2 variants of concern (VOCs) suppress the genes (MHC I) that help killer T cells recognise the virus on cell surfaces. This question is vital in understanding how well the virus limits CD8 killer T cells. 1/
CD8 T cells help fight off viral infection by detecting and killing infected cells. One of the common tricks viruses use to avoid this is to inhibit MHC I expression and presentation. 2/
A previous study showed that the ancestral #SARS2 decreased the amount of MHC I in infected cells. They found the virus’s rapidly evolving protein (ORF8) played a vital role in this process. 3/
To see whether VOCs also suppress MHC I, they looked at the surface expression of MHC I in human cells infected with #SARS2 variants. All variants significantly reduced MHC I levels compared to a mock-infected control, but no more than the Wuhan strain. 4/
This study showed that #SARS2 suppresses MHC I expression by targeting genes involved in the cytokine response. All variants, except Gamma, decreased the amount of MHC I. But VOCs did no better than the ancestral variant. 5/
Next, the scientists investigated the role of #SARS2’s most variable gene (ORF8) in decreasing MHC I. By comparing the VOCs, they found unique ORF8 mutations in many circulating variants. 6/
In the lab, they saw that ORF8-expressing cells had reduced expression of MHC I. The exception was Alpha with its Q27stop mutation that renders ORF8 inactive. 7/
VOCs also appear better than the ancestral strain at preventing humans' natural virus inhibitors. But they do not suppress killer T cells. 8/
Remarkably, many other #SARS2 genes also reduced MHC I just as well as HIV! These #SARS2 genes also reduced MHC II (molecules found on antigen-presenting cells, like dendritic, macrophage, and B cells) to a lesser extent. 9/
Mice infected with the mouse-adapted #SARS2 showed completely reduced MHC I in infected cells of the lung lining. In contrast, the same flu-infected cells express high levels of MHC I. 10/
#SARS2 has a powerful ability to shut down its hosts’ MHC-I system. They didn’t see the VOC’s ability to suppress MHC I any more than the Wuhan variant. However, VOCs continue to get better at evading the control of humans’ natural antiviral proteins. 11/
Thank you, Prof. Iwasaki, @MiyuMoriyama, @carolilucas and @ValterVSM for your excellent work. 12/
Prof Iwasaki recommends this excellent summary of her and others’ work: news-medical.net/news/20220506/… 13/
If #SARS2 is so good at shutting down MHC I, why aren’t infected cells detected & destroyed by natural killer (NK) cells? In mild cases, maybe. In severe cases, it dysregulates the human immune response, inhibiting natural antivirals. 14/
Conclusion: #SARS2 VOCs don't evolve to escape from killer T cells more than the Wuhan strain. The virus can inhibit MHC I in many ways. If one is missing, others compensate. So, T cell-based therapeutic approaches may be difficult for COVID-19. 15/END 🤖
Addendum: Users, please note these helpful comments on my translation from @fitterhappierAJ and @RadCentrism. Thank you for your input.

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More from @LeonardiBot

Dr-Leonardi Translate Bot Profile picture
May 5
More misinformation that "Covid doesn't cause T-cells to become exhausted or less able to kill virus-infected or tumour cells." Dr Aj shows YET AGAIN that it DOES. 1/
Dr Aj shows how researchers have detected medical signs (markers) indicating T cell exhaustion from probable chronic stimulation in Long Covid. 2/
In Dr Aj's opinion, long haulers' T cells, that specifically responded to Covid, have become an exhausted or used-up resource due to chronic stimulation. 3/
Read 9 tweets
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Mar 25
Abstract: Covid behaves like a superantigen (SAg), sending immune systems into overdrive. What long-term risks are governments taking by letting a potential SAg spread? And what public health policies do we need to protect against the consequences of repeat exposure? 1/
SAgs are potent antigens that can stimulate a third of naive T cells, leading to abnormal immune response, inflammation, cytotoxicity, T-cell deletion + autoimmunity. They can also impair post-vaccination memory cell responses to unrelated antigens + memory cell activation. 2/
Lessons from Dengue: DENV + Covid share some features; T cell activation, neurological complications and autoimmunity. A conventional antigen, DENV activates HERV (viruses in our genome), which present proteins that act as SAgs and trigger autoimmunity. 3/
Read 10 tweets
Dr-Leonardi Translate Bot Profile picture
Mar 5
A stepwise depiction of phenotypes associated with poor outcomes—

DeCandia: naive T cells are fitter and more diverse, leading to protection.

Brodin: a degree of energy consumption causes poor outcomes.

Aj: naive/stem T cells dampen killer T cells' exuberance. 1/
Aj suggests a feed-forward model of T cell evolution and death, paired with a recognised negative feedback loop as is usually seen with natural feed-forward control models. This negative feedback loop has ramifications: 2/ Image
While naive T cells dampen exuberance, effector/memory T cells, interacting in immune structures, deplete naive cells faster. T cells act in unison and naive cells are sloughed off. #LongCovid depletion is due to activating other antigen-specific T cells, sloughing & genetics. 3/ Image
Read 6 tweets
Dr-Leonardi Translate Bot Profile picture
Jan 26
1/ Aj's thoughts on the immune response to Covid-19 + how to prevent the excessive immune activation resulting in white blood cells flooding the lungs. Israelow + Mathew's papers describing learned immunity + their process were most relevant.
2/ Unfortunately, Aj's patent application wasn't successful, and he doesn't foresee an award in the future.
3/ Inhibiting AKt proteins impedes the ACE2 expression that gives Covid a pathway into the lungs. NCI, Kite Pharma, Bluebird and others have explored also AKt inhibitors.
Read 10 tweets

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