ACTRN12615001319561.

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-β, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses. V iral respiratory tract infections are the most common childhood infections worldwide, with close to 100% of children being infected during the first years of life. Whereas the vast majority of viral respiratory infections are mild and self-limiting, more severe disease leads to the hospitalization of about 3% of individuals in each birth cohort (1). In-hospital mortality rates are limited to <1% with intensive care support; still these infections account for 21% of childhood mortality worldwide (2, 3). The main viral pathogens causing lower respiratory tract infections are human respiratory syncytial virus (RSV), enteroviruses [including human rhinoviruses (HRV)], adenoviruses, human metapneumovirus, coronavirus, influenza, and parainfluenza viruses, with RSV being responsible for the majority of the hospitalized pediatric cases (4, 5).A number of risk factors including socioeconomic and environmental influences, preterm birth, chronic diseases, and immunosuppression are associated with more severe clinical presentation (6). However, ∼1 out of 1,000 children without any known risk factor will require intensive care support due to life-threatening manifestations of common viral respiratory infections. In the absence of established differences in pathogen virulence, we hypothesized that human genetic variation contributes to unusual susceptibility to severe disease due to common viruses. Supporting evidence is provided by a recent study, which showed that rare variants in IRF7 resulted in life-threatening influenza in an otherwise healthy child (7).We combined exome sequencing, transcriptomic analysis, and in vitro functional testing to identify and characterize potentially causal genetic variants in a prospective cohort of previously healthy children requiring intensive care support for common respiratory viral infections. We report the identification of a pathogen-restricted immunodeficiency due to loss-of-function variants in IFIH1, which result in defective innate recognition of RNA viruses, preventing the activation of an efficie...