In Vivo Conditions Enable IFNAR-Independent Type I Interferon Production by Peritoneal CD11b1 Cells upon Thogoto Virus Infection

This study investigated how type I interferon (IFN-I) can be induced independently of IFNAR-mediated feedback during Thogoto virus infection. Wild-type and innate immune-deficient mice (IFNAR⁻/⁻, MyD88⁻/⁻, TRIF⁻/⁻, MyD88⁻/⁻TRIF⁻/⁻, and MAVS⁻/⁻) were infected intraperitoneally in vivo, and IFN-β production was assessed in serum, peritoneal exudates, and organs by ELISA. To define cellular sources and signaling requirements, bone marrow-derived myeloid and plasmacytoid dendritic cells, as well as peritoneal exudate cells, were analyzed using in vitro infection, ex vivo culture, flow cytometry, reporter mice, MACS enrichment, and quantitative RT-PCR. THOV infection induced robust systemic IFN-β responses in vivo even in IFNAR-deficient mice, whereas comparable in vitro infections failed to do so, demonstrating a strict dependence on in vivo conditions. IFN production localized primarily to the peritoneal cavity and later the spleen. Using replication-incompetent but transcriptionally active THOV-derived virus-like particles, the authors showed that IFNAR-independent IFN induction required viral polymerase activity but not productive viral replication, as UV-inactivated particles were inactive. Genetic ablation revealed that IFN induction depended on MAVS-mediated RIG-I-like helicase signaling and was independent of TLR pathways. Reporter mouse analyses, supported by flow cytometry and transcript quantification, identified CD11b⁺ F4/80⁺ peritoneal myeloid cells as the dominant source of IFN-I. Collectively, the results define an alternative, tissue-restricted pathway enabling strong IFN-I production in vivo without IFNAR amplification.
(TMR)