Rabies Virus Infection Induces Type I Interferon Production in an IPS-1 Dependent Manner While Dendritic Cell Activation Relies on IFNAR Signaling

Abstract

As with many viruses, rabies virus (RABV) infection induces type I interferon (IFN) production within the infected host cells. However, RABV has evolved mechanisms by which to inhibit IFN production in order to sustain infection. Here we show that RABV infection of dendritic cells (DC) induces potent type I IFN production and DC activation. Although DCs are infected by RABV, the viral replication is highly suppressed in DCs, rendering the infection non-productive. We exploited this finding in bone marrow derived DCs (BMDC) in order to differentiate which pattern recognition receptor(s) (PRR) is responsible for inducing type I IFN following infection with RABV. Our results indicate that BMDC activation and type I IFN production following a RABV infection is independent of TLR signaling. However, IPS-1 is essential for both BMDC activation and IFN production. Interestingly, we see that the BMDC activation is primarily due to signaling through the IFNAR and only marginally induced by the initial infection. To further identify the receptor recognizing RABV infection, we next analyzed BMDC from Mda-5−/− and RIG-I−/− mice. In the absence of either receptor, there is a significant decrease in BMDC activation at 12h post infection. However, only RIG-I−/− cells exhibit a delay in type I IFN production. In order to determine the role that IPS-1 plays in vivo, we infected mice with pathogenic RABV. We see that IPS-1−/− mice are more susceptible to infection than IPS-1+/+ mice and have a significantly increased incident of limb paralysis.

Author Summary

Rabies virus (RABV) is a neurotropic RNA virus responsible for the deaths of the at least 40,000 to 70,000 individuals globally each year. However, the innate immune response induced by both wildtype and vaccine strains of RABV is not well understood. In this study, we assessed the pattern recognition receptors involved in the host immune response to RABV in bone marrow derived dendritic cells (DC). Our studies revealed that Toll like receptor (TLR) signaling is not required to induce innate responses to RABV. On the other hand, we see that IPS-1, the adaptor protein for RIG-I like receptor (RLR) signaling, is essential for induction of innate immune responses. Furthermore, we found that RIG-I and Mda-5, both RLRs, are able to induce DC activation and type I interferon production. This finding is significant as we can target unused pattern recognition receptors with recombinant RABV vaccine strains to elicit a varied, and potentially protective, immune response. Lastly, we show that IPS-1 plays an important role in mediating the pathogenicity of RABV and preventing RABV associated paralysis. Overall, this study illustrates that RLRs are essential for recognition of RABV infection and that the subsequent host cell signaling is required to prevent disease.