ABSTRACT
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 Aspergillus fumigatus challenge through the regulation of antifungal leukocyte responses. 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 interferons after A. fumigatus 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 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Conflict of Interests: The authors have declared that no conflict of interest exists.
1 Research in this study was supported in part by institutional startup funds to JJO in part through the Dartmouth Lung Biology Center for Molecular, Cellular, and Translational Research grant P30 GM106394 (PI: Bruce A. Stanton) and Center for Molecular, Cellular and Translational Immunological Research grant P30 GM103415 (PI: William R. Green). JJO was partially supported by a Munck-Pfefferkorn Award from Dartmouth College and NIH R01 AI139133 grant. Work by AR was partially funded by NIH R01 AI114647 grant. AR and RAC are Investigators in the Pathogenesis of Infectious Diseases supported by the Burroughs Wellcome Fund. The funders had no role in the preparation or publication of the manuscript.
↵2 Current Address: Loxo Oncology, Boulder, CO 80301
↵3 Current Address: Clemson University, Biological Sciences Department, Clemson, SC, 29634