2023,
Nature.
DOI:
10.1038/s41586-023-06331-x
A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection
Danillo G. Augusto, Lawton D. Murdolo, Demetra S. M. Chatzileontiadou, Joseph J. Sabatino, Tasneem Yusufali, Noah D. Peyser, Xochitl Butcher, Kerry Kizer, Karoline Guthrie, Victoria W. Murray, Vivian Pae, Sannidhi Sarvadhavabhatla, Fiona Beltran, Gurjot S. Gill, Kara L. Lynch, Cassandra Yun, Colin T. Maguire, Michael J. Peluso, Rebecca Hoh, Timothy J. Henrich, Steven G. Deeks, Michelle Davidson, Scott Lu, Sarah A. Goldberg, J. Daniel Kelly, Jeffrey N. Martin, Cynthia A. Vierra-Green, Stephen R. Spellman, David J. Langton, Michael J. Dewar-Oldis, Corey Smith, Peter J. Barnard, Sulggi Lee, Gregory M. Marcus, Jeffrey E. Olgin, Mark J. Pletcher, Martin Maiers, Stephanie Gras, Jill A. Hollenbach
Abstract:
Abstract Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1–4 . Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA ) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01–peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01 -mediated pre-existing immunity.
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2023-11-30 16:01:00
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#paper Augusto, D.G., Murdolo, L.D., Chatzileontiadou, D.S.M. et al. A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection. Nature 620, 128–136 (2023). https://doi.org/10.1038/s41586-023-06331-x.
大多数感染COVID-19的人会出现诸如发热、干咳、咽痛、嗅觉减退等典型临床症状。然而也有一部分人群即便感染了新冠病毒，也不会出现任何症状，这些人被称为无症状感染者。为探索这一现象的背后遗传机制中，本项研究使用了29,947名样本的高分辨HLA分型数据，发现人类白细胞抗原（HLA）基因座的变异可能是影响SARS-CoV-2感染者是否出现症状的关键因素。进一步的研究表明，这种遗传关联可能源于预先存在的T细胞免疫。来自携带HLA-B*15:01个体的大流行前样本中的T细胞对SARS-CoV-2 S蛋白衍生的主要免疫原性肽段NQKLIANQF表现出反应性。这些T细胞大多数呈现记忆表型，具有高度多功能性，并与季节性冠状病毒衍生的肽段交叉反应。除此之外，HLA-B15:01–肽段复合物的晶体结构，展示了NQKLIANQF和NQKLIANAF肽段被HLA-B15:01稳定并呈现的相似能力。最后，研究揭示了肽段结构相似性是HLA-B*15:01介导的预先存在免疫的分子基础，这种免疫是由高亲和力的公共T细胞受体的T细胞交叉反应性所决定的。综上所述，这项研究深入阐释了SARS-CoV-2无症状感染背后的遗传和免疫学机制，尤其是HLA-B*15:01基因座的作用。