MDA5 is an essential vita-PAMP sensor necessary for host resistance against Aspergillus fumigatus

RIG-I like receptors (RLR) are cytosolic RNA sensors that signal through the MAVS adaptor 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 challenge through the regulation of antifungal leukocyte responses. Activation of MDA5/MAVS signaling was driven by dsRNA from live serving as a key vitality-sensing pattern-recognition receptor. Interestingly, induction of type I interferons after challenge was only partially dependent on MDA5/MAVS signaling, whereas type III interferon expression was entirely dependent on MDA5/MAVS signaling. Ultimately, type I and III interferon signaling drove the expression of CXCL10, which is critical in resistance against invasive aspergillosis in transplant patients. Furthermore, the MDA5/MAVS-dependent interferon response was critical for the induction of optimal antifungal neutrophil killing of spores. In conclusion, our data broaden the role of the RLR family to include a role in regulating antifungal immunity against