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.
Highlights
The prevalence of autoreactive antibodies (auto-Ab) against innate immune IFNs in life-threatening COVID-19 patients indicates an autoimmune ambient accompanied by an overwhelmed IFN response dysregulated by pathogenic DNA from massive cell death caused by the robust virus infection, which is mediated through a cyclic GMP–AMP synthase and signaling effector stimulator of interferon gene (STING) pathway (Figure 2) [55,56,57,58]
Clinical outcomes of SARS-CoV2 infection are extensively broad in complication further with symptoms mimicking various inflammatory and autoimmune syndromes in severe COVID-19
Most of these symptomatic signs reflect immuno-pathological regulation through the epigenetic mechanisms, which facilitate us to explain the broadness and the dynamics of the clinical outcomes but shadow the focus of key immune determinants triggering the severity of COVID-19 [18,19,20,44,45,46,47,48,57]
Summary
The coronavirus disease 2019 (COVID-19), which has been declared a worldwide pandemic by the WHO since March of 2020, is caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3,4]. The clinical outcome of COVID-19 varies broadly among infected people, ranging from asymptotic infection and common cold-like sickness to a severe pneumonia leading to acute respiratory distress syndrome (ARS) and multi-organ complications that potentially have fatal prognosis [5,6,7,8]. As the virological branch focuses on diminishing viral spreading and virulence to cause disease, deciphering the genetic and especially epigenetic associations underlie severe COVID-19 will grasp the immunogenetic theme for severity prognosis in the host, providing manageable targets for early risk diagnosis and development of prophylactic and therapeutic remedies to face current pandemic [18,19,20]
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