Total predicted MHC-I epitope load is inversely associated with population mortality from SARS-CoV-2

A bstract 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. 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 highly probable MHC-I peptides. By weighing individual MHC allele-specific 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, gender demographics. and the proportions of the population that were over the age of 65 and overweight offered 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.