How loss-of-function mutations in IFIH1 contribute to infectious and/or inflammatory disease - a systematic review

The IFIH1 gene encodes for the cytoplasmic innate immune receptor Melanoma Differentiation-Associated protein 5 (MDA5) that detects viral double-stranded RNA to initiate type I interferon (IFN) responses. While gain-of-function mutations in IFIH1 have been linked with systemic inflammatory diseases, loss-of-function remains less well understood. This systematic review, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidance, explored how IFIH1/MDA5 loss-of-function affects susceptibility to virus infections and/or contributes to inflammatory diseases. Sixteen loss-of-function variants affecting IFIH1 were discussed across 33 studies. Loss-of-function variants were consistently associated with increased susceptibility and/or severity of virus infections, including severe acute respiratory syndrome coronavirus (SARS-CoV2) and human immunodeficiency virus (HIV). Several rare biallelic IFIH1 mutations lead to profound immunodeficiency, while heterozygous mutations associate with milder clinical presentations. Likely through dampening IFN responses, several variants protect from the development of inflammatory diseases, including type 1 diabetes and hypothyroidism. However, IFIH1 deficiency is also implicated in the development of inflammatory diseases, including inflammatory bowel disease. Moreover, the presence of inactivating anti-MDA5 antibodies may alter the clinical phenotypes and prognosis of dermatomyositis and infections with SARS-CoV2. Though their exact impact on MDA5 function has not been confirmed experimentally, anti-MDA5 antibodies may result in loss-of-function and impaired host defence against viruses. Loss of IFIH1/MDA5 activity has diverse effects on anti-viral immunity, associated damage and susceptibility to inflammatory disease, but also protection against organ-specific immune-mediated pathology. Findings highlight the importance of IFIH1 in immune regulation and warrant future studies exploring its potential as a diagnostic and therapeutic target.