Resistance To Lethal Ectromelia Virus Infection Requires Type I Interferon Receptor In Natural Killer Cells And Monocytes But Not In Adaptive Immune Or Parenchymal Cells

Type I interferons (IFN-I) are antiviral cytokines that signal through the ubiquitous IFN-I receptor (IFNAR). Following footpad infection with ectromelia virus (ECTV), a mouse-specific pathogen, C57BL/6 (B6) mice survive without disease, while B6 mice broadly deficient in IFNAR succumb rapidly. We now show that for survival to ECTV, only hematopoietic cells require IFNAR expression. Survival to ECTV specifically requires IFNAR in both natural killer (NK) cells and monocytes. However, intrinsic IFNAR signaling is not essential for adaptive immune cell responses or to directly protect non-hematopoietic cells such as hepatocytes, which are principal ECTV targets. Mechanistically, IFNAR-deficient NK cells have reduced cytolytic function, while lack of IFNAR in monocytes dampens IFN-I production and hastens virus dissemination. Thus, during a pathogenic viral infection, IFN-I coordinates innate immunity by stimulating monocytes in a positive feedback loop and by inducing NK cell cytolytic function.Author summary Type I interferon (IFN-I) is required for resistance to many viral infections and the IFN-I receptor IFNAR is ubiquitously expressed in most cells. Melo-Silva et al. show that resistance to mousepox, a highly lethal viral disease of mice, requires IFNAR in Natural Killer cells to promote optimal maturation and cytotoxicity, and in inflammatory monocytes for a positive feedback loop necessary to induce optimal IFN-I expression. However, intrinsic IFNAR is dispensable in adaptive lymphocytes or parenchymal cells indicating that for at least some viral infections, the critical anti-viral effects of IFN-I are restricted to cells of the innate immune system and are superfluous in other cell types.