Inborn Errors of Nucleic Acid Sensing and Type I Interferon Signaling Determine Viral Susceptibility in Humans

The innate immune system relies on nucleic acid (NA) sensors to detect viral infections and trigger type I interferon (IFN-I) responses, which are crucial for antiviral defense. NA pattern recognition receptors detect viral RNA or DNA within various cellular compartments, initiating antiviral signaling pathways. However, inherited deficiencies in these NA sensing mechanisms can result in increased susceptibility to severe viral infections. This review explores key genetic mutations affecting NA sensing and IFN-I pathways that predispose individuals to life-threatening viral diseases, including herpesviruses, respiratory viruses, enteroviruses, arboviruses, and vaccine-strain disseminated viral diseases. The identification of these monogenic defects in individuals afflicted by severe viral infections, along with the observed incomplete penetrance of these mutations, highlight the intricate interplay of the host's intrinsic, innate, and adaptive immune response with invading viral pathogens. These insights into the molecular basis of antiviral immunity not only underscore the clinical challenges associated with viral susceptibility but also offers the opportunity for personalized treatment strategies, including genetic screening, tailored vaccination protocols, and targeted antiviral therapies.