Given the ever-present global burden of influenza virus and newly emerging pathogens such as west nile, yellow fever, and dengue virus, the study of host-virus interactions can result in discoveries that have immediate impact on human health. We focus on the study of cellular recognition to RNA virus infection, the host response to their replication, and the means by which these viruses pirate the cellular machinery to avoid these processes. Our laboratory uses several techniques to study host-virus interactions including genetic manipulation of both host and pathogen to determine the effects on virus-induced cytokine signaling and viral fitness. We are presently working in the following areas.

1. Recognition of viral infection: The cellular response to virus demands that the infected cell be aware of the pathogen. This is achieved by cellular proteins which identify components of virus replication that are unique to the normal biological processes of the cell. These include RNA with exposed “uncapped” 5'-ends, cytoplasmic DNA, or the formation of double stranded RNA. We are presently trying to identify additional viral associated molecular patterns and to determine how these result in downstream cellular signaling.
2. The role of the IKK-related kinases in the cellular antiviral response: Following viral recognition, the cell responds with the secretion of Type I interferon (IFN-I). This is largely coordinated by cellular kinases which mediate the activation of a number of transcription factors. These transcription factors assemble into a multisubunit complex called the enhanceosome to induce IFN-I transcription. The result of IFN-I signaling is the upregulation of a wide variety of interferon stimulated genes (ISGs) which render cells resistant to viral infection. We study two kinases critical in the induction and signaling of IFN-I through the genetic manipulation of mice and subsequent in vivo virus infections.
3. The function of miRNA in the host response to virus infection: The general cellular response to virus infection as it relates to the induction of IFNb and the antiviral response has been well defined. Virus infection induces the transcriptional induction of over 150 virus-induced genes, many of which overlap with the transcriptional profiles of IFN-I treated cells. Included in this response are the induction of greater than 30 miRNAs. Unlike typical ISG products, miRNAs are small germ-line encoded RNA species which bind to cellular and viral RNA targets to inhibit translation in a sequence-specific manner. We study the contribution of miRNA species in the host response to RNA virus infection.
4. Viral antagonism of the IFN-I response: Although it is the adaptive response that ultimately clears virus infection, it is IFN-I signaling which must control both the spread and replication of the virus during the recruitment of the necessary adaptive machinery. The importance of IFN-I signaling with regards to inhibiting viral replication has been confirmed through a wide range of both in vitro and in vivo genetic studies. In addition, the necessity of IFN-I signaling can also be inferred from the fact that viruses often denote a portion of their genomic material to encode antagonistic proteins aimed at blocking the production or signaling of IFN-I. We use DNA rescue of replication competent vesicular stomatitis viral vectors to elucidate the mechanism of various flavivirus and orthomyxovirus proteins, both with respect to basic replication in addition to IFN-I antagonism.