My laboratory is interested in understanding the interactions between viruses and the host innate immune system that lead either to virus-induced disease or to resolution of the viral infection, with the ultimate goal of using this information to generate improved vaccines and therapeutics against virus-induced diseases. Our current studies are focused on mouse pathogenesis models using alphaviruses (Genus: Togaviridae, Family: Alphavirus), mosquito borne RNA viruses that are a significant cause of encephalitis and infectious arthritis in humans.

One major area of research emphasis within the laboratory is viral evasion of the antiviral type I interferon system, since interactions with the type I interferon system play a major role in determining whether the virus is able to successfully establish infection and cause disease. With this in mind, we are studying two distinct mechanisms by which alphaviruses avoid the type I interferon system. We have identified viral genetic determinants that regulate type I interferon induction and subsequently have a significant impact on virus-induced disease. The ultimate goal of this work is to characterize the mechanisms by which alphavirus nonstructural proteins antagonize the type I interferon system. We also have evidence the virus initially delivered by the mosquito is able to replicate within dendritic cells without inducing a type I interferon response, while virus derived from mammalian cells is a potent type I interferon inducer in these same cells. This phenotypic difference is mediated by the presence of high mannose N-linked glycans on the mosquito derived virus. Therefore, we are evaluating how viral glycosylation affects the early antiviral response as well as the virus's ability to initiate infection and cause disease in the newly infected vertebrate host. We are also using a model of virus-induced inflammatory disease to study viral interactions with the innate immune system that lead to virus-induced immune pathology. These studies utilize Ross River virus, an alphavirus that causes infectious arthritis in humans and a virus-induced joint/muscle disease in infected mice. We have used this system to study the role of specific host cell types and cytokines in mediating virus-induced disease. However, our real interest with this model is to identify and characterize the early steps in the disease process that ultimately lead to pathology. Therefore, we are evaluating the role of host pattern recognition molecules, such as Toll-like receptors (TLRs) in recognizing the virus and initiating the pathologic immune response.

Our ultimate goal with this work is to apply our findings on the molecular pathogenesis of alphaviruses toward the development of more effective alphavirus-based vaccine vectors. We have developed several novel alphavirus vectors and are in the process of evaluating these vectors for their ability to induce protective immune responses against a range of pathogens, including Rift Valley fever virus and the SARS coronavirus.