MDA5 Is an Essential Sensor of a Pathogen-Associated Molecular Pattern Associated with Vitality That Is Necessary for Host Resistance against Aspergillus fumigatus

RIG-I-like receptors (RLR) are cytosolic RNA sensors that signal through the MAVS adaptor to activate IFN responses against viruses. Whether the RLR family has broader effects on host immunity against other pathogen families remains to be fully explored. In this study, we demonstrate that MDA5/MAVS signaling was essential for host resistance against pulmonary Aspergillus fumigatus challenge through the regulation of antifungal leukocyte responses in mice. Activation of MDA5/MAVS signaling was driven by dsRNA from live A. fumigatus serving as a key vitality-sensing pattern recognition receptor. Interestingly, induction of type I IFNs after A. fumigatus challenge was only partially dependent on MDA5/MAVS signaling, whereas type III IFN expression was entirely dependent on MDA5/MAVS signaling. Ultimately, type I and III IFN signaling drove the expression of CXCL10. Furthermore, the MDA5/MAVS-dependent IFN response was critical for the induction of optimal antifungal neutrophil killing of A. fumigatus spores. In conclusion, our data broaden the role of the RLR family to include a role in regulating antifungal immunity against A. fumigatus.