Key Points
MDA5 is essential for maintaining host resistance against A. fumigatus.
MDA5 serves as a critical vitality sensor after fungal challenge.
MDA5 is essential for IFN-λ expression and antifungal neutrophil killing.
Visual Abstract
Abstract
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.
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Footnotes
This work was supported by institutional startup funds to J.J.O. in part through the Dartmouth Lung Biology Center for Molecular, Cellular, and Translational Research Core National Institute of General Medical Sciences (NIGMS) Grant P30 GM106394 (principal investigator: Bruce A. Stanton) and Center for Molecular, Cellular and Translational Immunological Research NIGMS Grant P30 GM103415 (principal investigator: William R. Green). J.J.O. was partially supported by a Munck-Pfefferkorn Award from Dartmouth College and National Institute of Allergy and Infectious Diseases (NIAID) R01 AI139133 grant. Work by A.R. was partially funded by NIAID R01 AI114647 grant. A.R. and R.A.C. 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.
The online version of this article contains supplemental material.
Abbreviations used in this article:
- BAL
- bronchoalveolar lavage
- BALF
- bronchoalveolar lavage fluid
- DKO
- double knockout
- FLARE
- fluorescent Aspergillus reporter
- GMM
- glucose-minimal medium
- GMS
- Grocott-Gomori methenamine silver
- IPA
- invasive pulmonary aspergillosis
- i.t.
- intratracheal(ly)
- LCMV
- lymphocytic choriomeningitis virus
- RLR
- RIG-I–like receptor
- vita-PAMP
- pathogen-associated molecular pattern associated with vitality.
- Received July 6, 2020.
- Accepted September 23, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
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