Abstract
Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).
Highlights
The spectrum of disease after infection by SARS-CoV-2 (COVID-19) may range from mild respiratory symptoms to a severe form of lung injury fulfilling acute respiratory distress syndrome (ARDS) criteria [1]
Study cohort 250 patients were admitted in intensive care unit (ICU) due to suspected or confirmed COVID-19
The steroid increased the expression of FOXO3 (Figure 5C) and IL6 (Figure 5D) only in cells with the TT variant. These results suggest that dexamethasone may alter the inflammatory response triggered by MDA5 activation in those patients with the TT variant of the gene
Summary
The spectrum of disease after infection by SARS-CoV-2 (COVID-19) may range from mild respiratory symptoms to a severe form of lung injury fulfilling acute respiratory distress syndrome (ARDS) criteria [1]. In these severe cases, systemic response to infection may be associated to multiorgan failure and death [2]. The human gene IFIH1, located in the reverse strand of chromosome 2, encodes MDA5, a helicase that acts as a cytoplasmatic virus receptor. The rs1990760 polymorphism encodes a variant of the IFIH1 gene (NM_022168: c.2836G>A [p.Ala946Thr]) that has been related to different susceptibility to viral infections and autoimmune disorders [5]. In experimental models of Coxsackie virus infection, TT variants in rs1990760 result in lower proinflammatory cytokine levels without a major reduction in viral clearance [6]
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