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.

COVID-19-associated acute respiratory distress syndrome (CARDS): Current knowledge on pathophysiology and ICU treatment – A narrative review

“…The “Severe COVID-19 genome-wide association study (GWAS) Group” identified changes in the locus mediating pro- and anti-inflammatory mediators and leukocyte chemotaxis affecting the severity of the disease [ 59 ]. High expression of tyrosine kinase (TYK)-2 and low expression of interferon-alpha/beta receptor beta chain (IFNAR2) were associated with life-threatening features of the disease [ 60 ]. Chemoattractant pathways and antiviral response mediated by type I interferon (IFN) signaling appear pivotal in the progression of COVID-19 [ 61 ].…”

Dysregulated Interferon Response Underlying Severe COVID-19

“…Contradictory results about type I IFN responses in COVID-19 patients may come from the disparity of criteria to define disease severity and different sampling times during the disease progression [ 25 ]. In addition, using large cohorts of COVID-19 patients in European countries, recent genome-wide association studies (GWAS) have significantly associated several critical genetic loci with severe COVID-19, which contain genetic regions spanning multiple genes that are centered in both chemokine and IFN signaling [ 26 , 27 ]. All these studies highlight the potential role of IFN signaling in determining the host susceptibility to SARS-CoV-2 infection and the progression of severe COVID-19 [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

“…Interferon signaling, for either IFN induction or action, is not a linear cascade but an interacting network, dynamically adapting to alternative and crosstalk with other cytokine signaling pathways [ 16 , 17 , 18 , 25 , 27 ]. For IFN induction signaling during an RNA-virus infection as in COVID-19, the typical pathway is triggered by viral RNA through membrane-bound or cytoplasmic receptors (TLRs or RLR, as in Figure 1 ) and culminated at IFN-regulatory factor (IRF)-3/7 activation and IFN expression.…”

“…However, the COVID-19 therapeutic effect of IFN treatments remains controversial, with respect to particularly the timing of administration and the pre-existing medical condition according to COVID-19 progression [ 25 , 78 ]. Interferon signaling has intricating crosstalk with multiple inflammatory cytokines, including TNF-α, IL-6, because they intersect in using some common intracellular signaling components [ 16 , 27 ]. In this context, the prophylactic effect of early IFN application may actually mitigate the CRS through the antiviral and anti-inflammatory effect of some epithelial-specific IFN subtypes.…”

SARS-CoV-2 meta-interactome suggests disease-specific, autoimmune pathophysiologies and therapeutic targets

“…Vaccines 2020, 8, 700. 4 Severe Covid-19 GWAS Group; Ellinghaus, D.; Degenhardt, F.; Bujanda, L.; Buti, M.; Albillos, A.; Invernizzi, P.; Fernández, J.; Prati, D.; Baselli, G.; et al Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N. Engl.…”