Polymorphisms in MHC-I protein sequences across human populations significantly impacts viral peptide binding capacity and thus alters T cell immunity to infection. Consequently, allelic variants of the MHC-I protein have been found to be associated with patient outcome to various viral infections, including SARS-CoV. In the present study, we assess the relationship between observed SARS-CoV-2 population mortality and the predicted viral binding capacities of 52 common MHC-I alleles ensuring representation of all MHC-I supertypes. Potential SARS-CoV-2 MHC-I peptides were identified using a consensus MHC-I binding and presentation prediction algorithm, called EnsembleMHC. Starting with nearly 3.5 million candidates, we resolved a few hundred high-confidence MHC-I peptides. By weighing individual MHC allele SARS-CoV-2 binding capacity with population frequency in 23 countries, we discover a strong inverse correlation between the predicted population SARS-CoV-2 peptide binding capacity and observed mortality rate. Our computations reveal that peptides derived from the structural proteins of the virus produces a stronger association with observed mortality rate, highlighting the importance of S, N, M, E proteins in driving productive immune responses. The correlation between epitope binding capacity and population mortality risk remains robust across a range of socioeconomic and epidemiological factors. A combination of binding capacity, number of deaths due to COPD complications, and the proportion of the population over the age of 65 offers the strongest determinant of at-risk populations. These results bring to light how molecular changes in the MHC-I proteins may affect population-level outcomes of viral infection.

中文翻译：

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MHC-1抗原决定簇的总预测负荷与SARS-CoV-2的死亡率成反比

整个人群中MHC-1蛋白序列的多态性会显着影响病毒肽的结合能力，从而改变T细胞对感染的免疫力。因此，已经发现MHC-1蛋白的等位基因变体与患者对包括SARS-CoV在内的各种病毒感染的预后有关。在本研究中，我们评估了观察到的SARS-CoV-2群体死亡率与52个常见MHC-1等位基因的预测病毒结合能力之间的关系，从而确保了所有MHC-1超型的代表性。使用称为EnsembleMHC的共有MHC-1结合和呈递预测算法，鉴定了潜在的SARS-CoV-2 MHC-1肽。从将近350万名候选人开始，我们解决了数百种高信心MHC-1肽。通过权衡23个国家/地区中各个人群的MHC等位基因SARS-CoV-2结合能力，我们发现预测的人群SARS-CoV-2肽结合能力与观察到的死亡率之间存在很强的逆相关性。我们的计算表明，衍生自病毒结构蛋白的肽与观察到的死亡率产生更强的联系，突显了S，N，M，E蛋白在驱动生产性免疫应答中的重要性。在一系列社会经济和流行病学因素中，表位结合能力与人群死亡风险之间的相关性仍然很强。结合能力，由于COPD并发症导致的死亡人数以及65岁以上人口的比例共同构成了高风险人群的决定因素。