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

Type I interferon (IFN-alpha/beta) induction upon viral infection contributes to the early antiviral host defense and ensures survival until the onset of adaptive immunity. Many viral infections lead to an acute, transient IFN expression which peaks a few hours after infection and reverts to initial levels after 24 to 36 h. Robust IFN expression often is conferred by specialized plasmacytoid dendritic cells (pDC) and may depend on positive-feedback amplification via the type I IFN receptor (IFNAR). Here, we show that mice infected with Thogoto virus (THOV), which is an influenza virus-like orthomyxovirus transmitted by ticks, mounted sustained IFN responses that persisted up to 72 h after infection. For this purpose, we used a variant of THOV lacking its IFN-antagonistic protein ML, an elongated version of the matrix (M) protein [THOV(Delta ML)]. Of note, large amounts of type I IFN were also found in the serum of mice lacking the IFNAR. Early IFN-alpha expression seemed to depend on Toll-like receptor (TLR) signaling, whereas prolonged IFN-alpha responses strictly depended on RIG-I-like helicase (RLH) signaling. Unexpectedly, THOV(Delta ML)-infected bone marrow-derived pDC (BM-pDC) produced only moderate IFN levels, whereas myeloid DC (BM-mDC) showed massive IFN induction that was IPS-1-dependent, suggesting that BM-mDC are involved in the massive, sustained IFN production in THOV(Delta ML)-infected animals. Thus, our data are compatible with the model that THOV(Delta ML) infection is sensed in the acute phase via TLR and RLH systems, whereas at later time points only RLH signaling is responsible for the induction of sustained IFN responses.