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.
Highlights
Type I interferon (IFN) was first identified as a ‘‘factor’’ that rendered cells resistant to viral infection [1]
We wanted to determine whether rabies virus (RABV) is able to inhibit IFN signaling in other cell types including dendritic cells (DC), which are known to induce the adaptive immune response
In order to check for type I IFN production, we first infected a variety of cell types including fibroblasts (BSR), neuronal cells (NA), macrophages (Raw264.7) and DCs (JAWSII) with a RABV vaccine strain-based vector, SPBN
Summary
Type I interferon (IFN) was first identified as a ‘‘factor’’ that rendered cells resistant to viral infection [1]. It is known that following viral infection, cells induce type I IFN, which in turn upregulates the expression of numerous antiviral proteins [2]. This class of cytokines is comprised of several genes including multiple IFN-a genes, a single IFN-ß gene, and the less well-defined IFN-v, -e, -t, -d, and -k (for review [3]). In addition to having antiviral functions, type I IFNs play a part in activating the adaptive immune response following infection [4,5,6]. Following maturation in the presence of type I interferon and GM-CSF, monocytederived DCs more effectively stimulate an antigen-specific CD8+ T cell response than when differentiated with GM-CSF alone [7]
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