BREAKING! COVID-19 Immunology: Could SARS-CoV-2 Be Depleting, Altering or Even Destroying CD8 Cells? New Australian Study Suspects So
: Australian scientist from Monash University, the University of Melbourne and James Cook University have made a disturbing discovery that infection with the SARS-CoV-2 coronavirus might compromise the activation of the CD8+ T-cell responses that would usually ameliorate disease and drive recovery.
The research findings are published on a preprint server and are currently being peer-reviewed. https://www.medrxiv.org/content/10.1101/2020.08.17.20176370v1
Lead researcher Dr Katherine Kedzierska from the department of Microbiology and Immunology at University of Melbourne and the rest of the co-researchers, by utilizing a combination of peptide prediction and in vitro peptide stimulation, found that while SARS-CoV-2 infection did stimulate CD4+ T-cell responses that were comparable to those seen with other viral infections, the CD8+ T cells that would usually target the virus were at extremely low prevalence and less than optimal phenotype for viral elimination.
It was estimated that the SARS-CoV-2-specific response was ten times lower than would usually be found for CD8+ T-cells targeting the viral Epstein-Barr Virus (EBV) or influenza A (IAV), as examples.
The study team says further research is needed to provide a more detailed understanding of CD8+ T-cell responses to the SARS-CoV-2 coronavirus since priming with an appropriate vaccine could be highly valuable in terms of optimizing protective CD8+ T-cell immunity.
While the majority of infections only cause mild disease and are short-lived, around 12 to 18% of patients with COVID-19 develop severe disease and require hospitalization.
What is even worrisome is that of those who do develop mild disease or are even asymptomatic, the underlying pathology may still be present.
To date, a lot remains unknown about the immune response to COVID-19, and an improved understanding is urgently needed if any immunopathology is going to be managed appropriately and vaccine development optimized.
It is generally known that virus-specific CD8+ T-cells play a role in clearing viral infection in the acute immune response to respiratory infection, where an established CD8+ T-cell memory response provides future protection against severe disease.
For example, survivors of the 2002-3 SARS-CoV-1 outbreak, for example, still maintain populations of CD4+ and CD8+ cells that are specific to the virus.
In the case of SARS-CoV-2, evidence suggests that virus-specific T-cells are being produced. A previous study by Kedzierska and team found CD4+ T-follicular helper cells and activated CD38+ HLA-DR+ CD8+ T-cells in the blood of patients with COVID-19 three days before recovery, suggesting that these cells were involved in resolving disease. (off course anomalies could also be attributed to mutating variants displaying other new characteristics.)
But there was also another study that showed that some of the SARS-CoV-2 specific CD8+ T cells in peripheral blood exhibited an “exhausted” phenotype, according to the researchers.
Thailand Medical News had reported on this in early July. https://www.thailandmedical.news/news/breaking!-covid-19-immunology-study-shows-high-levels-of-t-cells-with-significantly-altered-function-and-phenotype-in-severe-covid-19-patients
The researchers warn that it is a matter of urgency to develop a better understanding of the integrity of the acute CD8+ T-cell response in COVID-19 and how this impacts on disease outcome.
In the study, the researchers applied peptide prediction and in vitro peptide stimulation using peptides from the SARS-CoV-2 Spike, nucleocapsid, and membrane proteins.
The study team identified two novel HLA-A*02:01-restricted SARS-CoV-2 epitopes (A2/S269-277 and A2/Orf1ab3183-3191) in individuals with COVID-19.
Utilizing a peptide-HLA enrichment technique, the researchers determined the frequency and activation profiles of the SARS-CoV-2-specific CD8+ T-cell response in individuals with acute COVID-19 infection, convalescent individuals, and uninfected donors.
Detailed assessment of CD8+ T cell populations generated with the two novel epitopes showed that the more prominent A2/S269+ CD8+ T cell population was comparable to that seen in acute or convalescent patients positive for HLA-A*02:01.
Significantly however, although the CD8+ T cell population was higher than in uninfected HLA-A*02:01-positive donors, it was lower compared with the populations that are typically generated in response to EBV and IAV epitopes.
In addition, further analysis of the A2/S269+ CD8+ T-cells from recovered patients revealed that A2/S269+ CD8+ T-cells generally lacked the important activation markers CD38, HLA-DR, PD-1, and CD71.
The study team warns that while the CD4+ T cell response was similar to that found in other viral infections, the virus-activated CD8+ T cells that target SARS-CoV-2 peptides presented by the HLA-A*02:01 glycoprotein were both low in number and of a phenotype that was suboptimal for viral clearance.
They said, “These minimal activation profiles for epitope-specific CD8+ T-cells in early COVID-19 convalescence could possibly reflect suboptimal priming of A2/S269+ CD8+ T-cells in primary COVID-19.”
Detailed further investigation is needed to identify CD8+ T cell epitopes across many HLA class I alleles and SARS-CoV-2 proteins and better determine the CD8+ T-cell responses and their activation profiles in COVID-19.
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