Could HLA-type be the answer to individual differences in COVID-19 severity?

The Coronavirus disease 2019 (COVID-19) pandemic continues to have significant global impact and understanding the underlying biological causes of the disease and in particular why some patients suffer serious illness while others have mild or asymptomatic disease is of significant importance. COVID-19 is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and multiple factors are associated with disease outcomes. Research so far suggests human leukocyte antigen (HLA)-type could be a key differentiator between patients who experience different morbidity and mortality when infected with SARS-CoV-2. If this is the case, it could be possible to identify individuals at greater risk form the disease and explain differences in the epidemic trend in different countries. It could also help in development of novel vaccines to prevent COVID-19.

The HLA is a critical component of the viral antigen presentation pathway in humans and the HLA gene locus plays a fundamental role in human adaptive immunity. Genetic variability across the HLA alleles is known to be associated with outcomes in many different diseases and could be a key determinant in susceptibility to and severity of COVID-19. For example, HLA class I receptors which present antigen to cell-destroying cytotoxic T cells have three types, A, B and C. In any individual, each HLA class I type has an allele from each parent. Different alleles result in different variants of the HLA class I receptor, which can recognize different foreign proteins as antigen. Research has found that patterns of variation in HLA type can be seen within populations and countries, suggesting a given population will respond differently to a given virus depending on the HLA alleles found in that population.

Individual genetic variation in HLA-type may help to explain different immune responses to a virus across a population. HLA-type influences the T-cell-mediated response to viral infection, and is therefore implicated in the morbidity and mortality of SARS-CoV-2 infection. Patients with severe cases of COVID-19 have been shown to be suffering from a dysregulated adaptive immune response (Yu, 2020; Giamarellos-Bourboulis, 2020), which could be mediated via HLA type as individuals with different HLA types respond differently to the same viral antigen (Crux, 2017). A small study early in the COVID-19 pandemic found HLA-A*01:01 and HLA-A*02:01 correlated with number and severity of infections in Italy (Pisanti, 2020). In another study, researchers found homozygous HLA class I genes resulted in poor prognosis, except for specific HLA alleles which resulted in a lower risk of death (Shkurnikov, 2020). In a study of 82 Chinese patients, HLA type was associated with COVID-19 occurrence (Wang, 2020). Other studies have also found associations with HLA type and disease occurrence and morbidity, although at this stage most sample sizes are relatively small, and further research in large, varied populations is required.

This research will likely prove worthwhile. The differences in the morbidity and mortality of COVID-19 patients are striking with studies showing 18-30% of individuals are asymptomatic to SARS-CoV-2 infections (Warren, 2020) while others suffer severe and even fatal disease. The mortality rate is around 3.4% (Warren, 2020). Many factors have been implicated in the severity of disease from age, sex, and race to occupation (Mutambudzi, 2020). It’s possible HLA type intersects with other factors to result in a combined risk factor for severe disease. Identifying specific HLA-types that influence morbidity and mortality would allow identification of people and populations at greater risk if they were to become infected. Considering the relative ease and low cost of HLA-typing, a comprehensive understanding of HLA-type associations with population risk of disease could greatly improve public health measures to combat the COVID-19 pandemic (Nguyen, 2020).

Research is ongoing to understand how HLA-type may be associated with COVID-19 outcomes. The huge molecular variability of HLA alleles and single nucleotide polymorphisms (SNPs) means a significant effort is needed to truly understand the role of HLA-type in COVID-19 pathogenesis and epidemiology. Understanding who is most likely to become infected with SARS-CoV-2, and who is most at risk of severe outcomes and even death could help decision making around who gains access to early vaccines as they come available. As the most efficient way to combat viruses is via our own immune system, HLA peptide binding and T-cell response assays could help develop further effective vaccines to prevent spread of the disease entirely. As we begin to bring COVID-19 under control, thoughts turn to the potential role for HLA type in future disease outbreaks where an early understanding of how these receptors impact disease outcomes could help prevent unnecessary mortality via public health measures and develop new treatments specific to HLA-type.

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References

Crux NB, Elahi S. Human Leukocyte Antigen (HLA) and Immune Regulation: How do classical and non-classical HLA alleles modulate immune response to human immunodeficiency virus and hepatitis C virus infections? Front Immunol. 2017

Evangelos J.Giamarellos-Bourboulis. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. 2020

Mutambudzi M, Niedwiedz C, Macdonald EB, et al. Occupation and risk of severe COVID-19: prospective cohort study of 120 075 UK Biobank participants. Occupational & Environmental Medicine. 2020

Nguyen A, David JK, Maden SK, et al. Human leukocyte antigen susceptibility map for severe acute respiratory syndrome coronavirus 2. Journal of Virology. 2020

Pisanti S, Deelen J, Gallina AM, et al. Correlation of the two most frequent HLA haplotypes in the Italian population to the differential regional incidence of Covid-19. Journal of Translational Medicine. 2020

Shkurnikov, M. et al. Association of HLA class I genotypes with age at death of COVID-19 patients. 2020

Wang W, Zhang W, Zhang J, et al. Distribution of HLA allele frequencies in 82 Chinese individuals with coronavirus disease‐2019 (COVID‐19). 2020

Warren R, Birol I. Retrospective in silico HLA predictions from COVID-19 patients reveal alleles associated with disease prognosis. 2020

Warren R, Birol I. HLA predictions from the bronchoalveolar lavage fluid and blood samples of eight COVID-19 patients at the pandemic onset. 2020

Yu K, Jingjing H, Yongjian W, et al. Dysregulated adaptive immune response contributes to severe COVID-19. Cell Research. 2020