Participation of Single-Nucleotide Variants in IFNAR1 and IFNAR2 in the Immune Response against SARS-CoV-2 Infection: A Systematic Review

Abstract

Host genetic factors significantly influence susceptibility to SARS-CoV-2 infection and COVID-19 severity. Among these genetic factors are single-nucleotide variants (SNVs). IFNAR2 and IFNAR1 genes have been associated with severe COVID-19 in populations from the United Kingdom, Africa, and Latin America. IFNAR1 and IFNAR2 are subunits forming the type I interferon receptor (IFNAR). SNVs in the IFNAR genes impact protein function, affecting antiviral response and disease phenotypes. This systematic review aimed to describe IFNAR1 and IFNAR2 variants associated with COVID-19 susceptibility and severity. Accordingly, the current review focused on IFNAR1 and IFNAR2 studies published between January 2021 and February 2023, utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol. The electronic search was conducted in PubMed databases using Boolean operators and inclusion and exclusion criteria. Of the 170 literature pieces, 11 studies were included. We include case reports of rare SNVs, defined by minor allele frequency (MAF) < 1%, and genome-wide associated studies (GWAS). Variants in IFNAR1 and IFNAR2 could potentially be new targets for therapies that limit the infection and the resulting inflammation by SARS-CoV-2 infection.

Keywords: COVID-19; IFNAR1; IFNAR2; antiviral response; single-nucleotide variants.

Figure 1

Entry of SARS-CoV-2 into the cell via ACE2 and TMPRSS2. The endosome is formed by double-membrane vesicles where the coronavirus replicates. Viral RNA (ssRNA, dsRNA) is recognized by TLR3, TLR7, RIG-I, and MDA5. These receptors activate TRIF and MyD88, downstream TLRs, and MAVS downstream RIG-I and MDA5, starting in the interferon production pathway. When IRF3, IRF7, or NFkB are activated, they translocate to the nucleus and trigger the transcription of immunogens like inflammatory cytokines and IFN. The dotted line represents the transition to IFN signaling, beginning with IFN-I binding IFNAR to initiate JAK/STAT signaling. In silico assays propose that the A allele of rs2236757 in IFNAR2 increases the affinity of STAT3 to IFNAR1.

Figure 2

Flow diagram for the included studies.