The biogenesis of a paramyxovirus

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My long term objective is to understand virus biogenesis, explore the fundamental mechanisms of viral diseases and identify anti-viral therapeutic targets. Background: Viruses are important pathogens that cause increasing concerns on public health and global economy. Fundamental mechanisms by which viruses enter, assemble and leave host cells are crucial for understanding viral biology and reveal underlying processes essential for the host cell. I have built a single-molecule localization microscope (SMLM) with a resolution of 10 nm, about the size of a protein molecule. This microscope ensures high resolution imaging by a commercial unavailable stabilization system that can correct the imaging artifacts caused by unintended sample vibrations. By visualizing the virus assembly sites on host cells using this microscope, I found that proteins of a paramyxovirus, Nipah virus (NiV), come together in a random order, and not a stepwise, regulated process. This is different from other viruses, such as HIV. NiV can serve as a model system for viruses that do not follow the HIV pattern. In this five-year program, I will study the mechanisms for NiV assembly and release. My hypothesis is that the matrix protein of NiV drives the assembly and release of NiV by its interactions with host membrane lipids and the membrane fission machinery. My short term objectives are to: 1) determine the spatial and temporal mechanisms of the NiV assembly at the plasma membrane; 2) determine the role of membrane lipid domains in virus assembly by analyzing the spatial distribution and interaction dynamics between the virus assembly sites and lipid raft markers; 3) investigate the molecular mechanisms by which the membrane fission machinery helps virus release by mapping out the spatial organization and recruitment dynamics of the membrane fission components at the virus assembly sites. Impact: Analyzing the precise protein organizations in virus and cells can overturn past assumptions and make groundbreaking advances in virus research. In doing so my work may redirect the antivirus strategies and reveal new targets for the antivirus therapeutics. The work will also lead to technological advances in super-resolution microscopy and training of a diverse group of graduate (4) and undergraduate (5) students in multidisciplinary fields.