The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people worldwide and is the leading cause of mortality in Brazil in 2020 as well as early 2021. Clinical manifestations of COVID-19 disease range from no symptoms and mild flu-like symptoms to severe cases leading to hospitalization and death.
Nearly 30% of individuals infected with SARS-CoV-2 are asymptomatic but can still transmit the infection. This can be explained using a combination of epigenetic, genetic, and environmental factors such as exposure and previous infection. The identification of asymptomatic individuals is challenging as measuring different degrees of exposure is a complex task. However, these individuals may offer insights into the mechanisms of SARS-CoV-2 resistance and infection.
The human major histocompatibility complex (MHC) and leukocyte receptor complex (LRC) are good, natural candidates for studying the immune response against infectious agents like SARS-CoV-2. The LRC encodes leukocyte Ig-like receptors (LILRs), leukocyte-associated Ig-like receptors (LAIRs), and killer-cell Ig-like-receptors (KIRs). The MHC has many genes involved in presentation (HLA-DRB1), immune modulation (HLA-G, HLA-E, and antigen processing (TAP1 and TAP2). Since HLA and KIR loci show unusually high polymorphism and extensive paralogy, these genes are usually overlooked in genome-wide association studies (GWAS).
Based on recent observations, secondary transmission of SARS-CoV-2 to close contacts sharing a household was about 53%. Evaluating partners of symptomatic COVID-19 patients who shared the same bedroom without any protective measures such as masks is an efficient approach to analyze infection-resistant individuals who are highly exposed to the same strain of SARS-CoV-2.
Analyzing discordant Brazilian couples to study the variability in MHC and LRC genes
Researchers from Brazil recently investigated the variability in genes from the MHC and LRC, and the role played by them in SARS-CoV-2 infection and resistance. They analyzed a cohort comprising 86 Brazilian couples who were discordant for the infection. That is, one was infected while their partner who shares the household remained asymptomatic and seronegative for up to 6 months afterward, despite close exposure during the infection period. The ages and genetic ancestry proportions of the discordant partners were comparable. The study is published on the preprint server medRxiv*.
In order to study the association of variants within the LRC and MHC regions, the authors whole-exome sequenced the couples in the study cohort and applied a bioinformatics pipeline to recover the highly polymorphic genes and analyze them.
The researchers observed a minor impact in KIR genes and antigen-presentation genes associated with resistance. Genes related to immune modulation involved in NK cell killing activation/inhibition were found to have variants that may contribute to infection resistance. They hypothesized that individuals who produce more significant amounts of MICA, LILRB1, LILRB2, and lower amounts of MICB, would be more prone to SARS-CoV-2 infection.
“We observed little to no impact of polymorphisms in antigen-presentation genes and KIR genes in resistance or susceptibility to infection.”
Based on the study results and the authors’ hypotheses, quantitative differences in these molecules related to NK activity could contribute to SARS-CoV-2 resistance by downregulating NK cell cytotoxic activity in infected individuals but not in their resistant partners.
“We detected no relevant associations between KIR genes and SARS-CoV-2 infection for copy number, SNPs, and predicted protein sequences.”
To summarize, the authors performed a candidate region study to compare polymorphisms in the LRC and MHC regions in individuals infected with COVID-19 and their partners who were exposed to the virus but were asymptomatic and seronegative for COVID-19. Since all samples in this study were collected in early 2020, all couples studied were likely exposed to the same viral strain.
The findings suggest that genes with a role in innate and adaptive immune responses may play a vital part in viral resistance. Functional assays can provide a way to test this hypothesis of differential NK cell activity between SARS-CoV-2 infected individuals and resistant ones, involving MICB, MICA, and LAIR1/2 molecules.
“We hypothesize that individuals prone to produce higher amounts of MICA (possibly soluble), LILRB1, LILRB2, and low amounts of MICB, would be more susceptible to infection.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- “Immunogenetics of resistance to SARS-CoV-2 infection in discordant couples” Erick C. Castelli, Mateus V. de Castro, Michel S. Naslavsky, Marilia O. Scliar, Nayane S. B. Silva, Heloisa S. Andrade, Andreia S. Souza, Raphaela Neto Pereira, Camila F. B. Castro, Celso T. Mendes-Junior, Diogo Meyer, Kelly Nunes, Larissa R. B. Matos, Monize V. R. Silva, Jaqueline T. W. Wang, Joyce Esposito, Vivian R. Coria, Raul H. Bortolin, Mario H. Hirata, Jhosiene Y. Magawa, Edecio Cunha-Neto, Verônica Coelho, Keity S. Santos, Maria Lucia C. Marin, Jorge Kalil, Miguel Mitne Neto, Rui M. B. Maciel, Maria Rita Passos-Bueno, Mayana Zatz, medRxiv, 2021.04.21.21255872; doi: https://doi.org/10.1101/2021.04.21.21255872, https://www.medrxiv.org/content/10.1101/2021.04.21.21255872v1