Despite the high number of individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who develop coronavirus disease 2019 (COVID-19) symptoms worldwide, many exposed individuals remain asymptomatic and/or uninfected and seronegative. This could be explained by a combination of environmental (exposure), immunological (previous infection), epigenetic, and genetic factors. Aiming to identify genetic factors involved in immune response in symptomatic COVID-19 as compared to asymptomatic exposed individuals, we analyzed 83 Brazilian couples where one individual was infected and symptomatic while the partner remained asymptomatic and serum-negative for at least 6 months despite sharing the same bedroom during the infection. We refer to these as “discordant couples”. We performed whole-exome sequencing followed by a state-of-the-art method to call genotypes and haplotypes across the highly polymorphic major histocompatibility complex (MHC) region. The discordant partners had comparable ages and genetic ancestry, but women were overrepresented (65%) in the asymptomatic group. In the antigen-presentation pathway, we observed an association between HLA-DRB1 alleles encoding Lys at residue 71 (mostly DRB1*03:01 and DRB1*04:01) and DOB*01:02 with symptomatic infections and HLA-A alleles encoding 144Q/151R with asymptomatic seronegative women. Among the genes related to immune modulation, we detected variants in MICA and MICB associated with symptomatic infections. These variants are related to higher expression of soluble MICA and low expression of MICB. Thus, quantitative differences in these molecules that modulate natural killer (NK) activity could contribute to susceptibility to COVID-19 by downregulating NK cell cytotoxic activity in infected individuals but not in the asymptomatic partners.
MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals
Erick C. Castelli1,2*, Mateus V. de Castro3*, Michel S. Naslavsky3,4, 
Marilia O. Scliar3, Nayane S. B. Silva2, Heloisa S. Andrade2, Andreia S. Souza2, Raphaela N. Pereira2, Camila F. B. Castro2,5, Celso T. Mendes-Junior6, Diogo Meyer4, Kelly Nunes4, Larissa R. B. Matos3, Monize V. R. Silva3, Jaqueline Y. T. Wang3, Joyce Esposito3, Vivian R. Coria3, Raul H. Bortolin7, Mario H. Hirata7, Jhosiene Y. Magawa8, Edecio Cunha-Neto8,9,10, Verônica Coelho9,10, Keity S. Santos8,9,10, Maria Lucia C. Marin9,10, Jorge Kalil8,9,10, Miguel Mitne-Neto11, Rui M. B. Maciel11, Maria Rita Passos-Bueno3,4 and Mayana Zatz3,4*
- 1Department of Pathology, School of Medicine, São Paulo State University (UNESP), Botucatu, Brazil
- 2Molecular Genetics and Bioinformatics Laboratory–Experimental Research Unit, School of Medicine, São Paulo State University (UNESP), Botucatu, Brazil
- 3Human Genome and Stem Cell Research Center, University of São Paulo, São Paulo, Brazil
- 4Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo, Brazil
- 5Centro Universitário Sudoeste Paulista, Avaré, Brazil
- 6Departamento de Química, Faculdade de Filosofa, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil
- 7Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
- 8Departamento de Clínica Médica, Disciplina de Alergia e Imunologia Clínica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
- 9Laboratório de Imunologia, Instituto do Coração (InCor), LIM19, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, (HCFMUSP), São Paulo, Brazil
- 10Instituto de Investigação em Imunologia – Instituto Nacional de Ciências e Tecnologia-iii-INCT, São Paulo, Brazil
- 11Research and Development, Grupo Fleury, São Paulo, Brazil
https://www.frontiersin.org/articles/10.3389/fimmu.2021.742881/full
