Unlocking life-threatening COVID-19 through two types of inborn errors of type I IFNs

Abstract

Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying a few severe viral illnesses. Autoantibodies neutralizing type I IFNs due to rare inborn errors of autoimmune regulator (AIRE)–driven T cell tolerance were discovered in 2006, but not initially linked to any viral disease. These two lines of clinical investigation converged in 2020, with the discovery that inherited and/or autoimmune deficiencies of type I IFN immunity accounted for approximately 15%–20% of cases of critical COVID-19 pneumonia in unvaccinated individuals. Thus, insufficient type I IFN immunity at the onset of SARS-CoV-2 infection may be a general determinant of life-threatening COVID-19. These findings illustrate the unpredictable, but considerable, contribution of the study of rare human genetic diseases to basic biology and public health.

Activated STING in the thymus alters T cell development and selection leading to autoimmunity

“…Further investigation is needed to understand how interferon secretion in the thymus is regulated, particularly given recent studies that suggest loss of interferon expression in the thymus may lead to the generation of interferon autoantibodies that predispose to severe COVID-19 and other infections (39). In addition to nucleic acid sensing molecules such as STING, the transcriptional activator Autoimmune regulator (AIRE) may have a role in controlling interferon expression in TECs (40).…”

“…Further investigation is needed to understand how interferon secretion in the thymus is regulated, particularly given recent studies that suggest loss of interferon expression in the thymus may lead to the generation of interferon autoantibodies that predispose to severe COVID-19 and other infections (39). In addition to nucleic acid sensing molecules such as STING, the transcriptional activator Autoimmune regulator (AIRE) may have a role in controlling interferon expression in TECs (40). Interestingly, a number of different viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have been shown to directly target the thymic microenvironment and infect cells involved in thymocyte selection, including thymic epithelial cells (41, 42).…”

Inborn errors of immunity illuminate mechanisms of human immunology and pave the road to precision medicine

“…33,34 IEI associated with thymic stromal defects include those related to syndromes resulting from defective embryological processes that encompass structures of the midline, and specific genes critical to thymic development. For example, defects in forkhead box [36][37][38] For example, more than 80% of patients…”

“…In their review, Bastard et al. (6) also show how different IEI affecting central T ‐ cell tolerance illuminate the mechanism of development of auto ‐ Abs that neutralize type I interferon (IFN) 36‐38 . For example, more than 80% of patients with IEI in the alternative NF‐kB pathway carry neutralizing auto‐Abs to type I IFN 39 .…”

Type I interferon pathway genetic variants in severe COVID-19

“…IFN-I responses can also be impaired by autoimmunity. Although not consistently associated with susceptibility to viral diseases, the presence of IFN-I autoantibodies has been observed in critical COVID-19 patients with pneumonia ( Bastard et al, 2020 ; Casanova and Anderson, 2023 ; Manry et al, 2022 ). Bastard et al (2020) suggest IFN-I autoimmunity to be a cause of severe COVID-19 rather than a consequence of SARS-CoV-2 infection, even though it may intensify its effects.…”