In a recent study published in Nature, researchers describe findings from the COVID-19 Citizen Science Study, a large-scale study examining diversifications in human leukocyte antigen (HLA) in a prospective cohort that includes other people with mild coronavirus disease 2019 (COVID-19).
They invited 29,947 volunteer bone marrow donors with knowledge of high-resolution HLA genotyping to expand this prospective cohort and two independent cohorts.
Many studies targeting the genetic basis of differential COVID-19 outcomes have tested genetic associations with severe disease progression, primarily in hospitalized cohorts, for example, the multicenter Host Genetics initiative.
However, few studies have tested genetics in non-hospitalized, prospective and network cohorts. Studies that directly examined associations of HLA with infection had small cohorts and had pooled and inconclusive results.
Hundreds of genes govern human immune responses to disease, whose HLA variants have the most powerful associations with viral infections. This makes them applicable molecular targets for COVID-19 vaccine development.
People who express HLA-B*46:01 may be more vulnerable to COVID-19. In contrast, HLA-B*15:03 protects against COVID-19 by presenting highly conserved SARS-CoV-2 peptides to T cells.
More information on the effect of HLA diversifications on infectious diseases can only indicate the progress of potential vaccines and immunotherapies for COVID-19.
The existing study had a smartphone-based study design that helped researchers track COVID-19 symptoms and outcomes, adding positive effects of reverse transcription polymerase chain reaction (RT-PCR) testing of nearly 30,000 other people in the past genotyped HLA for five loci, HLA-A, -B, -C, -DRB1 and -DQB1.
In particular, they included knowledge of positive verification effects up to April 30, 2021, of other people known to belong to the “white” ethnic group. They retrieved their knowledge from a pre-existing knowledge base for medical studies called the National Marrow Donor Program (NMDP).
In addition, they contextualized the effects of mobile T reactivity examination, mobile T receptor repertoire (TCR), affinity, and structural implications for observed HLA associations.
In addition, the researchers tested the crystal structures of the HLA-B*15:01 molecule in a complex with seasonal coronavirus (CoV) peptides, for example, HKU1-CoV and OC43-CoV, at concentrations of five μM and ten μM.
The main finding of the study is that the HLA-B*15:01 allele was obviously linked to asymptomatic infection in participants who reported a positive SARS-CoV-2 test result.
Almost 10% of other people of European descent carry this common allele and remain asymptomatic after SARS-CoV-2 infection than those who do not.
Another important effect of HLA-B*15:01 homozygosity was that it increased the probability of remaining asymptomatic for SARS-CoV-2 eightfold. Asymptomatic patients in two independent study cohorts also had very similar frequency distributions of HLA-B*15:01.
In addition, the effects of the study showed that the HLA-DRB1*04:01 allele enhanced the HLA-B*15:01 effect when paired, as in other people of American descent who were called white.
By analyzing immunodominant epitopes in human peripheral blood mononuclear T cells or PBMCs from healthy donors before the pandemic, the authors observed that donor cells with the HLA-B*15:01 allele exposed to SARS-CoV-2 were reactive to the SARS-CoV-2 peak NQK-Q8 peptide, and peak cells showed a reminiscent pheype.
Thus, this amino acid series between seasonal CoVs and SARS-CoV-2 S-peptides explains the cross-reactivity of T lymphocytes.
The presence of high-affinity, cross-reminiscent T cells in unexposed donors further corroborated the relationship between the HLA-B*15:01 allele and asymptomatic COVID-19.
Other recent studies have also shown that SARS-CoV-2-specific memory T cells are enriched at the site of infection and temporarily aid the manifest onset of symptoms by secreting more interferon gamma (IFN-Ύ).
The S-peptides of SARS-CoV-2 and other CoVs, namely NQK-Q8 and NQK-A8, showed comparable stabilization of the HLA-B*15:01 molecule. In addition, HLA-B*15:01 presented these peptides in a structural conformation, providing a molecular basis for pre-existing immunity and cross-reactivity of T cells.
Most importantly, despite limited knowledge about HLA-B*15:01 epitopes discovered in SARS-CoV-2 patients, the effects of this study revealed that NQK-Q8, the main peptide candidate governing HLA-B*15:01-mediated T-cell cross-immunity with seasonal CoVs.
The effects strongly examine the role of the HLA-B*15:01 allele in mediating asymptomatic COVID-19 through pre-existing T-cell immunity due to prior exposure to other CoVs.
The understanding that HLA elegance I alleles play a role in early infection and the mechanisms underlying early viral clearance leading to asymptomatic SARS-CoV-2 infection has vital implications.
It becomes the framework for long-term studies aimed at refining vaccine progression and treatments for early diseases.
Augustus, D. et al. (2023) “A non-unusual HLA allele is linked to asymptomatic SARS-CoV-2 infection”, Nature. doi: 10. 1038/s41586-023-06331-x. https://www. nature. com/articles/s41586-023-06331-x#:~:text=Our discovery cohort (n = 1428, observed in two independent cohorts
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Neha is a virtual marketing professional founded in Gurugram, India. He holds a master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. He has delighted in preclinical studies as part of his assignment of studies in the Decomponent of Toxicology of the prestigious Central Institute of Drug Research (CDRI), Lucknow, India. He also has a certification in C programming.
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