Host Genetics at the Intersection of Autoimmunity and COVID-19: A Potential Key for Heterogeneous COVID-19 Severity

Abstract

COVID-19 presentation is very heterogeneous across cases, and host factors are at the forefront for the variables affecting the disease manifestation. The immune system has emerged as a key determinant in shaping the outcome of SARS-CoV-2 infection. It is mainly the deleterious unconstrained immune response, rather than the virus itself, which leads to severe cases of COVID-19 and the associated mortality. Genetic susceptibility to dysregulated immune response is highly likely to be among the host factors for adverse disease outcome. Given that such genetic susceptibility has also been observed in autoimmune diseases (ADs), a number of critical questions remain unanswered; whether individuals with ADs have a significantly different risk for COVID-19–related complications compared to the general population, and whether studies on the genetics of ADs can shed some light on the host factors in COVID-19. In this perspective, we discuss the host genetic factors, which have been under investigation in association with COVID-19 severity. We touch upon the intricate link between autoimmunity and COVID-19 pathophysiology. We put forth a number of autoimmune susceptibility genes, which have the potential to be additional host genetic factors for modifying the severity of COVID-19 presentation. In summary, host genetics at the intersection of ADs and COVID-19 may serve as a source for understanding the heterogeneity of COVID-19 severity, and hence, potentially holds a key in achieving effective strategies in risk group identification, as well as effective treatments.

C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

“…Host genetics also contributes to aberrant immunity in autoimmune diseases and susceptibility to infectious diseases in humans and such variants are often found in genes involved in the immune response and inflammation [44,45]. The current knowledge and our work confirm these findings in COVID-19 [41,43,45,57,58]. Autophagy genes have recently been proposed as susceptibility factors in COVID-19 [46].…”

NSAIDs/nitazoxanide/azithromycin repurposed for COVID-19: potential mitigation of the cytokine storm interleukin-6 amplifier via immunomodulatory effects

“…Alternatively, we have previously published two articles to justify the use of NSAIDs including diclofenac potassium and ibuprofen for early management of COVID-19 [ 32 , 33 ]. We suggested that NSAIDs might prevent, especially when early administered, or reverse COVID-19 associated hyperinflammatory response which is correlated with the immuno-pathologically induced SARS CoV-2 morbidity and mortality [ 5 ] and to prevent the cytokine induced lymphocyte distraction into or away from the lungs that is laboratory manifested through lymphopenia [ 32 ].…”

“…Interestingly and more clinically important, an exaggerated inflammatory response was described as the culprit of the majority of COVID-19 deaths and it was attributed to a weak, irregular or inhibited early interferon response to SARS CoV-2 infection that causes an excessive viral replication triggering this exaggerated inflammatory response and leading to unconstrained immune response which is responsible for COVID-19 associated mortality, rather than the virus itself [ 5–7 ].…”

Lung Protection vs. Infection Resolution: Interleukin 10 Suspected of Double-Dealing in COVID-19

“…For instance, it can be used to represent a variety of differences in viral genotypes, i.e., phylogenetic diversity, and putatively related endo-and phenotypes including those that may emerge during SARS-CoV-2 pandemic (127)(128)(129)(130). Instead of the viral genotype, host genetic risk factors of COVID-19 (131)(132)(133)(134) and their endotype and phenotype relations can be illustrated. Accordingly, endotypes can consist, for instance, in various immune evasion strategies and clinical phenotypes in any patient outcome.…”