Influenza is both a major human pathogen, causing approximately 50,000 deaths per year in the United States and a well-studied model system for cell entry by enveloped viruses. Influenza enters cells via a process of membrane fusion, but despite extensive study the mechanism by which influenza hemagglutinin catalyzes this process is not well understood. Experimental mutagenesis has yielded much data on the functional requirements of influenza fusion proteins, but we have no robust theory that could have predicted these results. This proposal seeks to develop a robust understanding of fusion peptide mechanisms sufficient to predict such mutations to hemagglutinin. We also wish to establish which elements of influenza entry are common to all membrane fusion, as modifications to the lipid environment can also promote or block fusion, and which may be virus-specific. We are developing high-performance simulation methods to analyze membrane fusion;in this work, we will use these methods to predict how mutations to influenza fusion peptides alter the virus's ability to infect cells and to investigate how lipid composition changes interact with these mutations to control viral infectivity. Computational predictions will be evaluated against experimental assays performed in the laboratory of collaborator Steinhauer.

Public Health Relevance

This project studies how influenza coat proteins interact with cell membranes to infect the cell. By studying how viral mutations can interfere with this process, we hope to uncover new strategies for antiviral treatment.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Chin, Jean
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University of Virginia
Schools of Medicine
United States
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Goronzy, I N; Rawle, R J; Boxer, S G et al. (2018) Cholesterol enhances influenza binding avidity by controlling nanoscale receptor clustering. Chem Sci 9:2340-2347
Zawada, Katarzyna E; Okamoto, Kenta; Kasson, Peter M (2018) Influenza Hemifusion Phenotype Depends on Membrane Context: Differences in Cell-Cell and Virus-Cell Fusion. J Mol Biol 430:594-601
Kasson, Peter; DiMaio, Frank; Yu, Xiong et al. (2017) Model for a novel membrane envelope in a filamentous hyperthermophilic virus. Elife 6:
Zawada, Katarzyna E; Wrona, Dominik; Rawle, Robert J et al. (2016) Influenza viral membrane fusion is sensitive to sterol concentration but surprisingly robust to sterol chemical identity. Sci Rep 6:29842
Lipsitch, Marc; Barclay, Wendy; Raman, Rahul et al. (2016) Viral factors in influenza pandemic risk assessment. Elife 5:
Rawle, Robert J; Boxer, Steven G; Kasson, Peter M (2016) Disentangling Viral Membrane Fusion from Receptor Binding Using Synthetic DNA-Lipid Conjugates. Biophys J 111:123-31
Domanska, Marta K; Dunning, Rebecca A; Dryden, Kelly A et al. (2015) Hemagglutinin Spatial Distribution Shifts in Response to Cholesterol in the Influenza Viral Envelope. Biophys J 109:1917-24
Pronk, Sander; Lindahl, Erik; Kasson, Peter M (2015) Coupled diffusion in lipid bilayers upon close approach. J Am Chem Soc 137:708-14
Pronk, Sander; Lindahl, Erik; Kasson, Peter M (2014) Dynamic heterogeneity controls diffusion and viscosity near biological interfaces. Nat Commun 5:3034
Fox, Daniel A; Larsson, Per; Lo, Ryan H et al. (2014) Structure of the Neisserial outer membrane protein Opa??: loop flexibility essential to receptor recognition and bacterial engulfment. J Am Chem Soc 136:9938-46

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