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How a specific gene variant protects against severe COVID-19 infection

Medicover Genetics Editorial Team |
January 20th 2022

The OAS region was identified as a COVID-19 risk locus in association studies of mainly individuals of European ancestry. The protective haplotype derived from Neanderthals in individuals of European ancestry spans the three genes OAS1, OAS2 and OAS3 on chromosome 12. Read more about this study under Article 2.

Article 1: SARS-CoV-2 spike T cell responses induced upon vaccination or infection remain robust against Omicron 

A recent paper reports that 70-80% of the T cell response is preserved in people infected with the Omicron variant offering protection from severe disease. The authors examined T cell responses in participants who had received one or two doses of the Ad26.COV2.S vaccine, two doses of the BNT162b2 mRNA vaccine, or who had recovered from infection. The results demonstrate that vaccination and infection induce a robust CD4+ and CD8+ T cell response that largely cross-reacts with Omicron, similar to other variants of concern, Beta and Delta, that carry fewer mutations. The limited effect of Omicron’s mutations on the T cell response suggests that vaccination or prior infection may still provide substantial protection from severe disease. Cross-reactive T cell responses acquired through vaccination or infection may contribute to apparent milder outcomes for Omicron observed in South Africa.

Article 2: Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19 

This study identified a specific gene variant that protects against severe COVID-19 infection. The OAS region was identified as a COVID-19 risk locus in association studies of mainly individuals of European ancestry. The protective haplotype (combination of alleles or to a set of single nucleotide polymorphisms (SNPs) found on the same chromosome) derived from Neanderthals in individuals of European ancestry is approximately 75 kb and spans the three genes OAS1, OAS2 and OAS3 on chromosome 12 (12q24.13). According to the researchers, the protective gene variant (rs10774671-G) determines the length of the protein encoded by the gene OAS1. Prior studies have shown that the longer variant of the protein is more effective at breaking down the SARS-CoV-2 virus (https://www.nature.com/articles/s41591-021-01281-1).

Article 3: Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts 

This paper reports that T cells from common colds cross-protect against infection with SARS-CoV-2. The researchers found that there were significantly higher levels of these cross-reactive T cells in the people who did not become infected, compared to the people who did become infected. These T cells targeted internal proteins within the SARS-CoV-2 virus, rather than the spike protein on the surface of the virus, to protect against infection. Current vaccines do not induce an immune response to these internal proteins. The researchers say that – alongside our existing effective spike protein-targeting vaccines – these internal proteins offer a new vaccine target that could provide long-lasting protection because T cell responses persist longer than antibody responses which wane within a few months of vaccination.  

Article 4: BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2 

A recent study published in Nature reports that blocking production of the protein BRD2, which regulates the ACE2 receptor, prevents the virus from infecting a variety of human cell types. The scientists screened 2,325 cellular proteins that they thought might affect COVID-19 infection by influencing the virus’s interaction with human cells. The authors determined that existing drugs targeting BRD2 can thwart COVID-19 infection in susceptible cell types, as well as in hamsters. However, the researchers caution that this new study is only a first step, and many more studies will be required to prove the safety and efficacy of any drug directed at BRD2 or other newly identified targets. 

Reference

[1] Keeton R et al. T cell responses to SARS-CoV-2 spike cross-recognize Omicron. Nature. 2022 Mar;603(7901):488-492. doi: 10.1038/s41586-022-04460-3. Epub 2022 Jan 31. Erratum in: Nature. 2022 Apr;604(7907):E25. PMID: 35102311; PMCID: PMC8930768. https://www.nature.com/articles/s41586-022-04460-3

[2] Huffman JE et al. Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19. Nat Genet. 2022 Feb;54(2):125-127. doi: 10.1038/s41588-021-00996-8. Epub 2022 Jan 13. PMID: 35027740; PMCID: PMC8837537. https://www.nature.com/articles/s41588-021-00996-8

[3] Kundu R et al. Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts. Nat Commun. 2022 Jan 10;13(1):80. doi: 10.1038/s41467-021-27674-x. PMID: 35013199; PMCID: PMC8748880. https://www.nature.com/articles/s41467-021-27674-x

[4] Samelson AJ et al. BRD2 inhibition blocks SARS-CoV-2 infection by reducing transcription of the host cell receptor ACE2. bioRxiv [Preprint]. 2021 Sep 20:2021.01.19.427194. doi: 10.1101/2021.01.19.427194. Update in: Nat Cell Biol. 2022 Jan;24(1):24-34. PMID: 33501440; PMCID: PMC7836110. https://www.nature.com/articles/s41556-021-00821-8

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