Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Sep 28:12:742881.
doi: 10.3389/fimmu.2021.742881. eCollection 2021.

MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals

Erick C Castelli  1   2 , Mateus V de Castro  3 , Michel S Naslavsky  3   4 , Marilia O Scliar  3 , Nayane S B Silva  2 , Heloisa S Andrade  2 , Andreia S Souza  2 , Raphaela N Pereira  2 , Camila F B Castro  2   5 , Celso T Mendes-Junior  6 , Diogo Meyer  4 , Kelly Nunes  4 , Larissa R B Matos  3 , Monize V R Silva  3 , Jaqueline Y T Wang  3 , Joyce Esposito  3 , Vivian R Coria  3 , Raul H Bortolin  7 , Mario H Hirata  7 , Jhosiene Y Magawa  8 , Edecio Cunha-Neto  8   9   10 , Verônica Coelho  9   10 , Keity S Santos  8   9   10 , Maria Lucia C Marin  9   10 , Jorge Kalil  8   9   10 , Miguel Mitne-Neto  11 , Rui M B Maciel  11 , Maria Rita Passos-Bueno  3   4 , Mayana Zatz  3   4
Affiliations

MHC Variants Associated With Symptomatic Versus Asymptomatic SARS-CoV-2 Infection in Highly Exposed Individuals

Erick C Castelli et al. Front Immunol. .

Abstract

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.

Keywords: COVID-19; HLA; MHC; MICA; MICB; SARS-CoV-2; asymptomatic; resistance.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
List of the genes optimized by the hla-mapper program in the Major Histocompatibility Complex (MHC).
Figure 2
Figure 2
The frequency of each candidate variant at the Major Histocompatibility Complex (MHC) associated with susceptibility to SARS-CoV-2 symptomatic infection or with asymptomatic and seronegative after exposure. COVID-19[+]: Patients with symptomatic COVID-19. COVID-19[-]: Individuals sharing the same bed with symptomatic patients (exposed individuals) and are asymptomatic and seronegative. P-value (1): Logistic regression comparing all COVID-19[+] and all COVID-19[-] individuals, controlling for sex, age, and genetic ancestry; P-value (2): Logistic regression comparing COVID-19[+] and COVID-19[-] individuals, controlling for age, and genetic ancestry; P-value (3): Fisher exact test, comparing COVID-19[+] or COVID-19[-] individuals with a population sample paired by gender and genetic ancestry. In green, P-values < 0.005; In yellow, P-value between 0.005 and 0.05.
Figure 3
Figure 3
The frequency of each candidate allotype and amino acid residue encoded in the Major Histocompatibility Complex (MHC) associated with susceptibility to SARS-CoV-2 symptomatic infection or with asymptomatic and seronegative after exposure. COVID-19[+]: Patients with symptomatic COVID-19. COVID-19[-]: Individuals sharing the same bed with symptomatic patients (exposed individuals) and are asymptomatic and seronegative. P-value (1): Logistic regression comparing all COVID-19[+] and all COVID-19[-] individuals, controlling for sex, age, and genetic ancestry; P-value (2): Logistic regression comparing COVID-19[+] and COVID-19[-] individuals, controlling for age, and genetic ancestry; P-value (3): Fisher exact test, comparing COVID-19[+] or COVID-19[-] individuals with a population sample paired by gender and genetic ancestry. In green, P-values < 0.005; In yellow, P-value between 0.005 and 0.05. Notes: (A) DOB*01:02 is the only HLA-DOB allotype carrying residue 18Q; (B) MICB*004, *024, *028 carry residue 75N (residue 75 in the full-length protein); (C) This residue is common to many HLA-A alleles, including A*23:01, A*25:01, A*26:01, *29:02, *30:01, *30:02, *31:01, *32:01, *33:01; (D) This residue is common to many HLA-A allotypes, including A*23:01, *29:02, *30:01, *30:02, *31:01, *32:01, *33:01; (E) This residue occurs in DRB1*03:01, *03:02, *04:01,*04:09, *13:03. rs9269942/T captures only a fraction of the sequences encoding K at position 101 from HLA-DRB1, since the composition of other surrounding variants, including indels, can produce the codon for K.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Oran DP, Topol EJ. Prevalence of Asymptomatic SARS-CoV-2 Infection : A Narrative Review. Ann Intern Med (2020) 173:362–7. doi: 10.7326/M20-3012 - DOI - PMC - PubMed
    1. Syangtan G, Bista S, Dawadi P, Rayamajhee B, Shrestha LB, Tuladhar R, et al. . Asymptomatic SARS-CoV-2 Carriers: A Systematic Review and Meta-Analysis. Front Public Heal (2021) 8:587374. doi: 10.3389/fpubh.2020.587374 - DOI - PMC - PubMed
    1. Johansson MA, Quandelacy TM, Kada S, Prasad PV, Steele M, Brooks JT, et al. . SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open (2021) 4:1–8. doi: 10.1001/jamanetworkopen.2020.35057 - DOI - PMC - PubMed
    1. Ellinghaus D, Degenhardt F, Bujanda L, Buti M, Albillos A, Invernizzi P, et al. . Genomewide Association Study of Severe Covid-19 With Respiratory Failure. N Engl J Med (2020) 383:1522–34. doi: 10.1056/NEJMoa2020283 - DOI - PMC - PubMed
    1. Pairo-Castineira E, Clohisey S, Klaric L, Bretherick AD, Rawlik K, Pasko D, et al. . Genetic Mechanisms of Critical Illness in COVID-19. Nature (2021) 591:92–8. doi: 10.1038/s41586-020-03065-y - DOI - PubMed

Substances