Inborn errors of autophagy underlying severe viral infections in humans

Inborn errors of immunity can underlie susceptibility to severe viral infection in humans. and the majority relate to defective induction of or response to antiviral type I interferon (IFN). However there is increasing awareness of defects in other cellular processes, that can predispose to severe infectious disease. Recently, defects in autophagy-related genes or -processes have been demonstrated to predispose to life-threatening viral diseases, including defects in autophagy-related genes in patients with herpes simplex virus and varicella zoster virus infections in the central nervous system, as well as impairment of noncanonical antiviral immunity in critical COVID-19. However, the molecular mechanisms and complex intersections between autophagy, metabolism, cell death, and inflammation, and how defects in autophagy-related proteins may interfere with these cellular processes, are only now starting to emerge. This review presents the current knowledge on inborn errors of autophagy discovered in patients with severe viral infection and discusses some of the remaining knowledge gaps in our understanding of how autophagy processes act against viruses, how immunopathology and lack of viral control ensues when they fail, and how these insights may be translated into clinical medicine.