Germline Genetic Variants of Viral Entry and Innate Immunity May Influence Susceptibility to SARS-CoV-2 Infection: Toward a Polygenic Risk Score for Risk Stratification

Abstract

The ongoing COVID-19 pandemic caused by the novel coronavirus, SARS-CoV-2 has affected all aspects of human society with a special focus on healthcare. Although older patients with preexisting chronic illnesses are more prone to develop severe complications, younger, healthy individuals might also exhibit serious manifestations. Previous studies directed to detect genetic susceptibility factors for earlier epidemics have provided evidence of certain protective variations. Following SARS-CoV-2 exposure, viral entry into cells followed by recognition and response by the innate immunity are key determinants of COVID-19 development. In the present review our aim was to conduct a thorough review of the literature on the role of single nucleotide polymorphisms (SNPs) as key agents affecting the viral entry of SARS-CoV-2 and innate immunity. Several SNPs within the scope of our approach were found to alter susceptibility to various bacterial and viral infections. Additionally, a multitude of studies confirmed genetic associations between the analyzed genes and autoimmune diseases, underlining the versatile immune consequences of these variants. Based on confirmed associations it is highly plausible that the SNPs affecting viral entry and innate immunity might confer altered susceptibility to SARS-CoV-2 infection and its complex clinical consequences. Anticipating several COVID-19 genomic susceptibility loci based on the ongoing genome wide association studies, our review also proposes that a well-established polygenic risk score would be able to clinically leverage the acquired knowledge.

Implications of the Immune Polymorphisms of the Host and the Genetic Variability of SARS-CoV-2 in the Development of COVID-19

“…Recent studies have identified deleterious variants involved in IFN type I signaling, including variants of TLR-3; transcription factors, such as STAT1 and STAT2; interferon regulatory factors, such as IRF1 and IRF7; and IFN-α receptors, such as IFNAR1 e IFNAR2, are associated with inadequate immune responses after vaccination as well as the most severe cases of COVID-19. This is reflected at the cellular level, where pDCs cannot produce IFNs during SARS-CoV-2 infections [16,185]. In another work, TLR-3, IRF3, and IRF7 variants were detected in patients with severe COVID-19.…”

“…More particularly, TLR-7 and TLR-8 recognize single-stranded RNA (ssRNA), while intermediate RNA (double-stranded RNA or dsRNA) produced during viral replication is detected by TLR-3 [179][180][181]. TLR signal transduction implicates myeloid differentiation factor 88 (MyD88) and TIR domain-containing adaptor-inducing interferon-beta (TRIF), activating NF-kB, type I IFN regulatory factor (IRF)3, and IRF7, leading to a type I IFN response [16,182].…”

“…TLR SNPs have been found in neoplastic, autoimmune, and infectious diseases. For instance, rs3775291 polymorphism of TLR-3 was associated with autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and sarcoidosis [16]. In the case of SARS-CoV-2 infection, rs3775291 (L412F) and rs3775290 polymorphisms have caused recognition of SARS-CoV-2 RNA to be decreased [14,183].…”

“…Its activation leads to signal transduction that activates the NFκB, IRF3, and JAK-STAT pathways. It is probable that SARS-CoV-2 is also detected by these cytosolic RNA sensors, and it could be suggested that loss-of-sense mutations in these sensors or the proteins associated with their transduction signaling can also cause poor viral clearance, as observed with other coronaviruses [16,199,200].…”

“…As some examples of PRRs, we can mention polymorphisms of Toll-like receptor (TLR)-3 or molecules involved in their signaling pathways [14][15][16] as well as polymorphisms of RIG-1 and MDA5, which are associated with susceptibility to SARS-CoV-2 infection due to lack for recognition of viral RNA and disrupted signaling pathway for IFN production.…”