Cell entry and innate immune recognition of enveloped viruses.

The overarching goal of my research program is to gain a mechanistic understanding at the molecular level of how important pathogens interact with their host cells during infection. We seek to understand: How do enveloped viruses assemble and recognize host cells? How do enveloped viruses deliver their genome into the cytoplasm? How are innate immune responses to viral nucleic acids generated, amplified and regulated? We employ a diverse set of complementary approaches including X-ray crystallog raphy, electron microscopy, solution biophysics, fluorescence microscopy and cell biological approaches to understand the mechanisms that underlie these processes in molecular-level detail. Our projects have important potential applications in global health. We will develop two specific projects: 1--Enveloped viruses deliver their genome into the cell by fusing the viral and cellular membranes. The molecular steps required for membrane fusion are still poorly understood. We propose a comprehens ive analysis of the mechanism and kinetics of membrane fusion of various enveloped viruses using biophysical and cell biological approaches. 2--The mechanism of viral RNA recognition by the innate immune system remains poorly understood. We have shown that MDA5 coats viral RNA, forming filaments that nucleate the assembly of multimeric signaling platforms. We will determine the structures and kinetic assembly parameters of MDA5 filaments, and their relationship to signaling activity.