Mda5/MAVS signaling is essential for resistance against Aspergillus fumigatus

Abstract

Abstract Type I and III interferons act as important activators of antifungal neutrophil response in the lungs. The RIG-I like receptor (RLR) family, including RIG-I and Mda5, are cytosolic RNA sensors that signal through the MAVS adaptor in order to activate interferon responses against viruses. Whether the RLR family has broader effects on host immunity against other pathogen families remains to be fully explored. Herein we demonstrate that Mda5/MAVS signaling was essential for host resistance against pulmonary Aspergillus fumigatus challenge through the regulation of antifungal leukocyte responses. Aspergillus fumigatus induction of type I interferons was partially dependent on Mda5/MAVS signaling, while type III interferon expression was entirely dependent on Mda5/MAVS signaling. Activation of the interferon pathway was driven by prolonged exposure to fungal spores, rather than germ tubes. Ultimately, interferon signaling drove the expression of CXCL9 and CXCL10, SNPs in the latter are associated with invasive aspergillosis in human patients. Our data suggest a broader role of the RLR family in the regulation of innate immunity to include invasive fungal infections.