Arbovirus Evasion of Type I Interferon Induction

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DESCRIPTION: The initial interaction between viruses and the innate immune system plays a major role in determining whether the virus will successfully establish infection. This may be particularly important for arboviruses, which include a number of biodefense related and emerging pathogens, since many of these viruses initially replicate in dendritic cells following inoculation by the arthropod vector. In preliminary studies, when alphaviruses, including Venezuelan equine encephalitis virus (VEE), a class B biodefense pathogen, were grown in mammalian cells, these viruses were potent inducers of type IIFN responses in infected myeloid dendritic cells (mDC). However, when these same viruses were grown in mosquito cells, they efficiently infected the mDCs, but failed to induce type I IFN responses in these cells. Furthermore, preliminary studies also indicated that this difference in type I IFN induction was due to the presence of high mannose glycans on the surface of the mosquito cell derived virus. As ligation of DC-SIGN, a mannose binding C-type lectin that mediates infection of mDCs by mosquito-derived alphaviruses, can suppress dendritic cell activation by Toll-like receptors (TLRs), this suggests that the mosquito-derived virus may interact with DC-SIGN or some other mannose binding protein to inhibit, interferon induction in the infected mDC. Furthermore, this may allow arthropod borne alphaviruses to avoid the induction of antiviral immune responses in the initially infected dendritic cell following delivery from the mosquito vector and thereby enhance the virus's ability to establish infection in the vertebrate host. In order to characterize this potentially important pathway of immune evasion, we propose to: 1) Perform a detailed analysis on the differences between mosquito and mammalian cell derived alphaviruses with respect to type I IFN induction, 2) Determine whether this effect is specific to type I interferons or extends to the induction of other cytokines by the infected mDCs, and 3) Evaluate the role of viral glycosylation and/or interactions with DC-SIGN in mediating this effect. The studies outlined in this application will form the basis for additional studies designed to: 1) characterize the mechanism by which mosquito derived viruses avoid the induction of antiviral responses in infected mDCs, and 2) use small animal models to evaluate the whether the decreased interferon induction by mosquito cell derived viruses affects the ability of these viruses to establish infection and cause disease.