Alphavirus Evasion of Type I Interferons

Alphaviruses are mosquito transmitted viruses that cause either severe arthritis or encephalitis. A critical stage that determines whether or not alphavirus infection will result in disease is the early interaction of the virus with the host following delivery from the mosquito vector. Of particular importance are interactions between mosquito derived virions and myeloid dendritic cells (mDC's) within the skin and draining lymph node. Therefore a focus of these studies was to evaluate if alphaviruses derived from either mosquito or mammalian cells interacted differently with mDC's. Our results revealed mosquito-cell-derived Ross River virus and Venezuelan Equine Encephalitis virus (mos-RRV and mos-VEE) more efficiently infected mDC's when compared to the same viruses grown in mammalian cells (mam-RRV and mam-VEE). However, mos-RRV and mos-VEE infection poorly induced type I interferons (IFN-αβ) when compared to mam-RRV and mam-VEE, suggesting that mosquito-cell-derived alphaviruses could either avoid or inhibit antiviral responses from infected mDC's. A major difference between mammalian and mosquito grown viruses is that mosquito-cell-derived virus particles exclusively incorporate terminal mannose N-linked glycans onto their glycoproteins, while mammalian-cell-derived viral glycoproteins incorporate complex, hybrid, and terminal mannose oligosaccharides. Differential IFN-αβ induction was linked to glycosylation since mDC's infected with viruses grown in mammalian cells that produce virions with only mannose glycans induced less IFN-αβ than mDC's infected with viruses grown in mammalian cells with complex glycans. Additional studies suggested that mos-RRV did not actively suppress mDC IFN-αβ production, since co-infection of mos-RRV with mam-RRV did not inhibit IFN-αβ responses. We next generated a panel of RRV glycan deficient viruses to identify the role for each N-linked glycan in IFN-αβ production. The panel revealed that E2 glycans on mam-RRV, but not mos-RRV, were required for robust IFN-αβ responses following mDC infection. These data suggest that poor IFN-αβ responses from mDC's following mos-RRV infection is attributed to a lack of complex glycans on the virion envelope. In summary, these data provide new insight into how mosquito-borne viruses evade IFN-αβ responses which may aid in their ability to establish infection