How the SARS-CoV-2 Omicron subvariant evolved to evade host T-cell immunity

In a recent article published in the journal PNASResearchers have found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants of concern (VOCs), especially omicron, have acquired mutations in the body as well as , are investigating whether CD8+ T cell-mediated immunity has evolved to evade.Resistant spike (S) protein Neutralizing antibody (nAbs).To this end they sought evidence in vitro and live Inhibition of major histocompatibility complex class I (MHC-I) upregulation in SARS-CoV-2 infected cells.

study: Enhanced inhibition of MHC-I expression by SARS-CoV-2 Omicron subvariants. Image Credit: Starshaker / Shutterstock.com

Background

MHC-I presents virus antigen For activation of CD8+ cytotoxic T lymphocytes (CTL). Once activated, these cells kill and eliminate virus-infected cells throughout the human body.

Several viruses have developed the ability to block MHC-I processing. For example, SARS-CoV-2 uses its open reading frame 8 (ORF8) protein to autophagically degrade MHC-I molecules to evade CTL surveillance.

Several studies conducted within the first three months of the 2019 coronavirus disease (COVID-19) pandemic reported that SARS-CoV-2 rapidly evolved its ORF8 gene.To date, it remains unclear whether this evolution enhanced the ability of SARS-CoV-2 to shut down MHC-I and subsequently evade antigen-specific memory CD8+. T cells Immunity conferred by previous infection or COVID-19 vaccination.

About research

In the current study, researchers investigated the potential SARS-CoV-2 alpha, beta, gamma, and delta VOCs and three variants of interest (VOIs), including epsilon B.1.427/B.1.429, and iota/B. are analyzing. .1.526, down-regulating the MHC-I pathway;

Up to 965 sequences of Omicron and other SARS-CoV-2 lineages were downloaded from various sources such as the Global Initiative for Sharing All Influenza Data (GISAID) database. We performed an ORF8 amino acid sequence alignment to identify non-synonymous mutations in SARS-CoV-2 variants, resulting in differential MHC-I regulation.

A standard polymerase chain reaction (PCR)-based mutagenesis method was used to generate seven SARS-CoV-2 envelope (E), membrane (M), and ORF8 expression mutants. We used these mutants to determine whether variant-specific mutations altered the MHC-I downregulation ability of the SARS-CoV-2 ORF8 protein.

Calu-3 and HEK293T cells were used to assess the effect of SARS-CoV-2 infection on MHC-I expression 2 days after infection.in order to live In the study, male C57BL6 mice were infected intranasally with 1 × 10^Five Plaque-forming units (PFU) of SARS-CoV-2 or influenza virus A/Puerto Rico/8/34.

Investigation result

Although ancestral SARS-CoV-2 strains potently repressed MHC-I surface expression, pleomicron VOCs evolved only to some extent to regulate the MHC-I pathway. All SARS-CoV-2 variants have the potential to suppress MHC-I expression, but the Omicron subvariant has the highest ability to suppress surface MHC-I expression due to her T9I mutation in the E protein. was related.

Eight non-synonymous mutations and two deletions from 16 SARS-CoV-2 variants were implicated in MHC-I regulation of ORF8. Furthermore, we found that the premature stop codon at the Q27 position of the Omicron B.1.1.7 subvariant truncated the length of ORF8, likely altering its function. None of these mutations or deletions were conserved among viral lineages, thus suggesting that these variant-specific mutations were acquired independently during the evolution of SARS-CoV-2. .

MHC-I upregulation was completely abolished in SARS-CoV-2 infected cells, indicating that SARS-CoV-2 viral proteins potently inhibited MHC-I upregulation in cells.In contrast, influenza virus infection markedly upregulated MHC-I expression in vitro.

Conclusion

SARS-CoV-2 uses multiple strategies to suppress MHC-I expression. Moreover, MHC-I downregulation by SARS-CoV-2 was found to impair her CTL recognition of infected cells for killing and priming of CD8 + T cells.

Interestingly, the ancestral strain of SARS-CoV-2 was fully equipped to escape CD8+ T cell-mediated immunity. Thus, although this strain was not under evolutionary pressure to optimize downregulation of MHC-I expression, it was subject to greater pressure to evolve and evade nAb- or type I interferon-induced immunity. I was receiving

MHC-I evasion by SARS-CoV-2 remains an important viral strategy to combat host immunity and provides important insights into SARS-CoV-2 pathogenesis and evolution. These findings may help predict challenges in discovering CD8 T-cell-based therapeutics against COVID-19.

In addition to evading nAbs and significantly mutating the S protein for improved transduction, all Omicron subvariants optimized evasion from T-cell recognition. This property, albeit in part, allows these variants to cause breakthrough infections and reinfections, even in largely vaccinated populations. Nevertheless, the consequences of enhanced MHC-I inhibition by Omicron variants remain unclear.