Mda5/MAVS are essential for host resistance against Aspergillus fumigatus

Abstract

Abstract Type I and III interferons act as important activators of antifungal neutrophil response in the lungs. RIG-I like receptors (RLR) are cytosolic RNA sensors that signal through the MAVS adaptor in order to activate interferon responses against viruses. Whether this pattern-recognition receptor 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. Interesting, induction of type I interferons after A. fumigatus challenge was only partially dependent on Mda5/MAVS signaling, while 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. Importantly, we found that polymorphisms in Ifih1 and Mavs were associated with the incidence of invasive pulmonary aspergillosis in a human HSCT cohort. Moreover, polymorphisms in the Ifih1 gene alter the inflammatory response induced in patients with invasive pulmonary aspergillosis, which include interferon-responsive chemokines. In conclusion, our data broaden the role of the RLR family in the regulating innate immunity during infection to include a role in immunity against Aspergillus fumigatus in both mice and humans.