Thogoto Virus Infection Induces Sustained Type I Interferon Responses That Depend on RIG-I-Like Helicase Signaling of Conventional Dendritic Cells

This study investigated the mechanisms underlying type I interferon (IFN) induction during Thogoto virus (THOV) infection using a recombinant virus lacking the IFN-antagonistic ML protein [THOV(ΔML)]. Mice, including wild-type and innate immune signaling–deficient strains (IFNAR⁻/⁻, MyD88⁻/⁻TRIF⁻/⁻, and IPS-1⁻/⁻), were infected in vivo, and serum IFN levels, viral loads, and survival were assessed. In parallel, bone marrow–derived myeloid dendritic cells (BM-mDC) and plasmacytoid dendritic cells (BM-pDC) were infected in vitro to identify cellular sources of IFN. THOV(ΔML) infection induced unusually high and sustained systemic IFN-α/β responses lasting up to 72 h, even in the absence of IFNAR signaling. Genetic ablation studies showed that early IFN induction partially involved Toll-like receptor pathways, whereas sustained IFN production strictly depended on the RIG-I–like helicase adaptor IPS-1. Viral replication was required for IFN induction, as UV-inactivated virus failed to elicit responses. Unexpectedly, BM-mDC, but not BM-pDC, were the dominant producers of type I IFN, and this response was IPS-1 dependent. Collectively, the results identify myeloid dendritic cells and IPS-1–mediated sensing as central drivers of sustained type I IFN responses during THOV infection.
(TMR)