Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and the elderly worldwide. Despite that, there is no licensed RSV vaccine and only limited therapeutics exists. RSV primarily infects epithelial cells of the respiratory tract and replicates in the cytoplasm. Viral proteins traffic to the apical cell surface where they assemble into virus filaments and bud. However, the mechanism of virus filament formation and budding is poorly understood, neither is the role of viral filaments versus the budded virus. Budding is an essential step in the life cycle of all enveloped viruses; however, the way by which viruses complete the process and free themselves from the plasma membrane presents a biophysical problem. A great number of viruses were shown to recruit the host’s cellular ESCRT fission pathway. Nevertheless, it has been demonstrated that RSV budding is independent of the ESCRT pathway and therefore studies of RSV have the potential to reveal a new paradigm for membrane fission and virus release. The proposed research focuses on the viral and cellular requirements during RSV assembly and budding. The minimal RSV viral proteins essential for filament formation and budding are fusion (F), matrix (M), nucleoprotein (N), and phosphoprotein (P), therefore all of the above will be used for screening against the human proteome. The screen will eventually lead to cellular protein linking RSV to host machinery utilized for its assembly and release. In parallel, RSV mutants that differ in assembly and budding efficiency compared to WT due to impaired binding to cellular factor will be identified. The new interactions discovered will lead to better understanding the mechanism behind RSV assembly and budding and will shed light on alternative mechanisms of viral release. The ultimate outcome of my research will be generating attenuated RSV for future vaccine development and discovering new targets for antiviral drugs industry.
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