Do monogenic inborn errors of immunity cause susceptibility to severe COVID-19?

Abstract

The SARS-CoV-2 virus, which causes COVID-19, has been associated globally with substantial morbidity and mortality. Numerous reports over the past year have described the clinical and immunological profiles of COVID-19 patients, and while some trends have emerged for risk stratification, they do not provide a complete picture. Therefore, efforts are ongoing to identify genetic susceptibility factors of severe disease. In this issue of the JCI, Povysil et al. performed a large, multiple-country study, sequencing genomes from patients with mild and severe COVID-19, along with population controls. Contrary to previous reports, the authors observed no enrichment of predicted loss-of-function variants in genes in the type I interferon pathway, which might predispose to severe disease. These studies suggest that more evidence is needed to substantiate the hypothesis for a genetic immune predisposition to severe COVID-19, and highlights the importance of considering experimental design when implicating a monogenic basis for severe disease.

Figure 1. Defects in innate antiviral signaling linked with increased SARS-Cov-2 disease severity.

(A) The type I IFNs are crucial to innate immune responses, and individuals with IEI may carry higher risk for severe COVID-19. Inherited defects associated with SARS-CoV-2 pathogenicity in the Zhang et al. study (13) (red) contrasts with the findings from Povysil et al. (14) (blue). However, other studies also show that acquired, male-predominant production of anti-IFN antibodies increases SARS-CoV-2 pathogenicity (yellow). More evidence is needed to establish a genetic immune predisposition to severe COVID-19. (B) Experimental design differences in the Zhang et al. and Povysil et al. studies include sample size and comparator groups. *P < 0.05 versus comparator cases. When implicating a monogenic basis for severe disease, best practices involve increasing the sample size, assessing variation across all genes as opposed to a subset, and distinguishing association from cause. Asx, asymptomatic; ER, endoplasmic reticulum; IFNAR, interferon-α/β receptor; ISRE, interferon-sensitive response element; IRF, interferon regulatory factor; IKK, IκB kinase; Jak, Janus kinase; NF, nuclear factor; STING, stimulator of interferon genes; SARS, severe acute respiratory syndrome; STAT, signal transducer and activator of transcription; TBK, TANK-binding kinase; TLR, Toll-like receptor; TRAF, TNF receptor–associated factor; TRIF, TIR-domain-containing adapter–inducing interferon-β; Tyk, tyrosine kinase; y, years.