117 : Toll-like receptor and RIG-I like helicase crosstalk is essential to protect against lethal infection with vesicular stomatitis virus

Abstract

Toll-like receptors (TLR) and RIG-I like helicases (RLH) have been implemented in the induction of protective type I interferon (IFN-I) responses after infection with single-stranded RNA encoded vesicular stomatitis virus (VSV). MyD88Trif−/− and Cardif−/− deficient mice devoid of either TLR or RLH dependent signaling, respectively, showed moderately enhanced susceptibility to lethal VSV infection upon intravenous challenge. To clarify the redundancy of both sensing mechanisms and the potential role of other recognition systems in VSV infection MyD88TrifCardif−/− deficient mice (MyTrCa−/−) were generated. Surprisingly, MyTrCa−/− mice were as sensitive to VSV infection as IFN-I receptor deficient mice, even after challenge with very low viral doses (200 pfu) and died within 1–2 days. Indeed, VSV infected triple deficient mice did not mount IFN-I responses, as evidenced by ELISA analysis of serum samples and monitoring of IFN-induced genes. Vaccination of MyTrCa−/− mice with modified vaccinia virus Ankara, which is known to trigger IFN-I responses to some extent TLR and RLH independently, conferred prolonged survival upon VSV infection. Furthermore, adoptive transfer of 10[7] bone marrow (BM) cells in vitro cultivated in the presence of Flt-3L that contain approximately 30% plasmacytoid DC (pDC) prolonged survival of VSV infected triple deficient mice by 2–3 days. Interestingly, adoptive transfer of 107 purified BM-pDC extended survival by 4–6 days, whereas adoptive transfer of conventional DC had no effect. Furthermore, BM chimeric MyTrCa−/− mice that were reconstituted with wild-type BM (WT > MyTrCa−/−) showed an improved survival upon VSV infection. Notably, the survival of MyTrCa−/− > WT chimeric mice was similarly extended as observed for WT > MyTrCa−/−mice. In conclusion our data indicate that VSV induces protective IFN-I responses that depend on TLR and RLH crosstalk on th e level of irradiation sensitive as well as irradiation resistant cells. pDC triggering seems to play an essential role to promote initial survival, whereas is not sufficient to confer full protection.