Immunogenetic Association Underlying Severe COVID-19

Abstract

SARS-CoV2 has caused the current pandemic of new coronavirus disease 2019 (COVID-19) worldwide. Clinical outcomes of COVID-19 illness range broadly from asymptotic and mild to a life-threatening situation. This casts uncertainties for defining host determinants underlying the disease severity. Recent genetic analyses based on extensive clinical sample cohorts using genome-wide association studies (GWAS) and high throughput sequencing curation revealed genetic errors and gene loci associated with about 20% of life-threatening COVID-19 cases. Significantly, most of these critical genetic loci are enriched in two immune signaling pathways, i.e., interferon-mediated antiviral signaling and chemokine-mediated/inflammatory signaling. In line with these genetic profiling studies, the broad spectrum of COVID-19 illness could be explained by immuno-pathological regulation of these critical immunogenetic pathways through various epigenetic mechanisms, which further interconnect to other vital components such as those in the renin-angiotensin-aldosterone system (RAAS) because of its direct interaction with the virus causing COVID-19. Together, key genes unraveled by genetic profiling may provide targets for precisely early risk diagnosis and prophylactic design to relieve severe COVID-19. The confounding epigenetic mechanisms may be key to understanding the clinical broadness of COVID-19 illness.

Keywords: COVID-19; chemokine signaling; epigenetic regulation; genome-wide association; interferon signaling.

Figure 1

Interferon and chemokine signaling pathways are centrically enriched by key Immunogenetic determinants revealed by recent studies focusing on severe COVID-19 cohorts. Major genes associated with COVID-19 were pooled from several recent immunogenetic studies [22,23,24,31]. The protein-protein interaction networks were performed using a STRING program [20]. The centrically enriched chemokine receptor genes in Chr. 3p21.31, which are regulated by both RAAS and TLR signaling pathways critically in chemokine signaling of inflammatory response, is associated with severe COVID-19 by multiple GWAS studies and highlighted using a yellow cross. Abbreviations: ACE2, angiotensin-converting enzyme 2; AGT, angiotensin; AGTR1, AGTII receptor type 1; CCR, C-C chemokine receptor; CXCR, C-X-C chemokine receptor; IRF, IFN-regulatory factor; IFNAR, IFN-α/β receptor subunit; MAS1, OAS, 2′-5′-oligoadenylate synthase; TBK1, TANK-binding kinase 1; TICAM1, TLR, Toll-like receptor; TMPRSS2, transmembrane protease serine 2; TYK2, non-receptor tyrosine-protein kinase; XCR, Chemokine XC receptor.

Figure 2

Dysfunctional interferon (IFN) and renin-angiotensin system (RAS) responses leading to severe COVID19. SARS-CoV2, the virus of COVID19, evolves in optimizing its infectivity and contagiousness to induce a weak antiviral innate immune IFN response during its acute phase of infection especially in the susceptible patients due to seniority, gender and existing medical conditions. SARS-CoV2 adopts angiotensin-converting enzyme 2 (ACE2), a critical and multirole component of the body RAS, as a major viral receptor expressed in multiple cell types. The progressive infection of the virus from pneumocytes to BV cells exaggerates RAS imbalance provoking proinflmmation, CRS and massive cell death (pyroptosis) catastrophized with viral spreading, which further provokes coagulopathy/fibrosis (as in Kawasaki syndrome) and autoimmune reactions against IFNs and RAS components. All these collectively lead to a complicated syndrome including systemic virus infection in multiple organs and functional deterioration of RAS plus compounding immunopathies and neurological manifestation. Abbreviations: AGTII, angiotensin II; AP1, activator protein 1 transcription factor; ARD, acute respiratory disease; AT1R, AGTII receptor type 1; BV, blood vessel; CRS, cytokine release syndrome; ISRE, IFN signaling responsive element; ISGF3, IFN-stimulated gene factor 3; NSP, non-structural proteins; RLR, retinoic acid-inducible gene-I-like receptors; pDNA, pathogenic DNA; STING, stimulator of interferon genes; TF, tissue factor.