Human genetics of SARS-CoV-2 infection and critical COVID-19

Abstract

Background: During the past 2 years, studies on patients with SARS-CoV-2 infection have revealed rare inborn errors of immunity (IEIs) in type interferon (IFN) pathways underlying critical COVID-19 pneumonia. This has provided insights into pathophysiological mechanisms and immune signaling circuits regulating antiviral responses to SARS-CoV-2 and governing the susceptibility to and outcome of SARS-CoV-2 infection in humans.

Objectives: In this review, the current knowledge on IEIs underlying critical COVID-19 is presented, and the clinical implications of these findings for individualized prophylaxis and treatment are outlined.

Sources: The review is based on a broad literature search, including primarily studies on whole-exome sequencing, and to a lesser extent genome-wide association studies, of patients with critical COVID-19, as well as retrospective descriptive studies of the SARS-CoV-2 disease course in individuals with known IEIs.

Content: The review describes the discovery of monogenic IEI in 9 genetic loci related to the production or responses to type I IFN in patients with critical COVID-19 pneumonia and the surprising finding of phenocopies of these, represented by neutralizing autoantibodies to type IFN in a significant proportion of patients with critical pneumonia, particularly in elderly men, and further enriched in patients with lethal disease course. Moreover insights gained from studies on SARS-CoV-2 infection, disease course, and outcome in patients with known IEI is presented. Finally, some hypotheses for a possible genetic basis of autoimmune, inflammatory, and long-term complications of SARS-CoV-2 infection are presented and discussed.

Implications: Uncovering IEIs underlying critical COVID-19 or other severe SARS-CoV-2 disease manifestations provides valuable insights into the basic principles of antiviral immune responses and pathophysiology related to SARS-CoV-2 infection. Such knowledge has important clinical implications for identification of susceptible individuals and for diagnosis, prophylaxis, and treatment of patients to reduce disease burden and improve preparedness against viral pandemics with known or emerging viruses in the future.

Keywords: COVID-19; Inborn error of immunity; Innate immunity; Interferon; MIS-C; SARS-CoV-2.

Fig. 1

Major cellular pathways in innate viral sensing and interferon induction in response to SARS-CoV-2 infection. Early after viral infection, viral nucleic acids in the form of single-stranded (ss)RNA or double-stranded (ds)RNA of the viral genome or replication intermediates are recognized by cytosolic or membrane-bound pattern recognition receptors (PRRs). These include the endosomal Toll-like receptors (TLR)3 and TLR7 recognizing dsRNA and ssRNA, respectively. In the cytosol, RIG-I and MDA recognize 5′triphosphorylated RNA species. These events trigger major signalling pathways, most notably governed by and dependent on the transcription factors NF-κB and interferon (IFN) regulatory factors (IRFs), inducing the production of type I IFN and proinflammatory cytokines. Type I IFN acts in an autocrine and paracrine manner by binding to cognate receptors composed of IFNAR1 and IFNAR2 and signal through the JAK-STAT pathway to induce an antiviral program through expression of numerous IFN-stimulated genes. Molecules with known genetic defects conferring susceptibility to SARS-CoV-2 infection as described in the main text are marked with a red asterisk. The figure was generated in Biorender.