TIR-Domain-Containing Adapter-Inducing Interferon-β (TRIF)-Dependent Antiviral Responses Protect Mice against Ross River Virus Disease

Ross River virus (RRV) is the major mosquito-borne virus in the South Pacific region. RRV infections are characterized by arthritic symptoms, which can last from several weeks to months. Type I interferon (IFN), the primary antiviral innate immune response, is able to modulate adaptive immune responses. The relationship between the protective role of type I IFN and the induction of signaling proteins that drive RRV disease pathogenesis remains poorly understood. In the present study, the role of TIR-domain-containing adapter-inducing interferon-β (TRIF), an essential signaling adaptor protein downstream of Toll-like receptor (TLR) 3, a key single-stranded RNA (ssRNA)-sensing receptor, was investigated. We found that TRIF(−/−) mice were highly susceptible to RRV infection, with severe disease, high viremia, and a low type I IFN response early during disease development, which suggests the TLR3-TRIF axis may engage early in response to RRV infection. The number and the activation level of CD4(+) T cells, CD8(+) T cells, and NK cells were reduced in TRIF(−/−) mice compared to those in infected wild-type (WT) mice. In addition, the number of germinal center B cells was lower in TRIF(−/−) mice than WT mice following RRV infection, with lower titers of IgG antibodies detected in infected TRIF(−/−) mice compared to WT. Interestingly, the requirement for TRIF to promote immunoglobulin class switch recombination was at the level of the local immune microenvironment rather than B cells themselves. The slower resolution of RRV disease in TRIF(−/−) mice was associated with persistence of the RRV genome in muscle tissue and a continuing IFN response.