Uncovering alterations in the murine interferon response due to dsRNA mycovirus during Aspergillus fumigatus infection

Abstract Aspergillus fumigatus is a mold that causes an array of diseases, the most severe form being invasive aspergillosis which occurs in highly immunocompromised individuals. We demonstrated that tissue-resident alveolar macrophages are critical for maintaining host resistance against Aspergillus fumigatus due to their role in the early type I/III interferon response. Specifically, CD11c-Cre x Mavs fl/flmice have a decreased interferon response and survival outcomes when challenged with A. fumigatus, which can be functionally restored via adoptive transfer of wild-type SiglecF +alveolar macrophages. Why alveolar macrophages are potent inducers of the type I/III interferon response after Aspergillus fumigatus challenge remains elusive. Here, we demonstrate that TGF-beta metabolically programs alveolar macrophages to be potent interferon inducers via enhanced dependency on oxidative phosphorylation and peroxisome biogenesis. The type I/III interferon responses were partially related to the inability of alveolar macrophages to recognize mycoviral double-stranded RNA (dsRNA). Aspergillus fumigatus strains infected with polymycovirus 1 (PmV1) are shown to induce a robust type I/III interferon responses both in vitro and in vivo. Critically, Mda5/MAVS-dependent interferon response can still be induced in a fungal dsRNA independent manner, which warrant further explorations. In this study we identified key metabolic traits of alveolar macrophages which enable robust Mda5/MAVS signaling necessary for initiating the Aspergillus fumigatus induced interferon response, which maintains host resistance against this ubiquitous mold, through both fungal dsRNA-dependent and -independent mechanisms.