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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM098304-01A1
Application #
8294116
Study Section
Biochemistry and Biophysics of Membranes Study Section (BBM)
Program Officer
Chin, Jean
Project Start
2012-04-01
Project End
2017-01-31
Budget Start
2012-04-01
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$284,561
Indirect Cost
$94,561
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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
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
Pronk, Sander; Lindahl, Erik; Kasson, Peter M (2015) Coupled diffusion in lipid bilayers upon close approach. J Am Chem Soc 137:708-14
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
Fox, Daniel A; Larsson, Per; Lo, Ryan H et al. (2014) Structure of the Neisserial outer membrane protein Opa₆₀: loop flexibility essential to receptor recognition and bacterial engulfment. J Am Chem Soc 136:9938-46
Gregory, Sonia M; Larsson, Per; Nelson, Elizabeth A et al. (2014) Ebolavirus entry requires a compact hydrophobic fist at the tip of the fusion loop. J Virol 88:6636-49
Pronk, Sander; Lindahl, Erik; Kasson, Peter M (2014) Dynamic heterogeneity controls diffusion and viscosity near biological interfaces. Nat Commun 5:3034
Larsson, Per; Kasson, Peter M (2014) Lipid converter, a framework for lipid manipulations in molecular dynamics simulations. J Membr Biol 247:1137-40
Russell, Colin A; Kasson, Peter M; Donis, Ruben O et al. (2014) Improving pandemic influenza risk assessment. Elife 3:e03883
Pronk, Sander; Pall, Szilard; Schulz, Roland et al. (2013) GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics 29:845-54

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