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 #
3R01GM098304-03S1
Application #
8849714
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
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
$55,905
Indirect Cost
$20,522
Name
University of Virginia
Department
Physiology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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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
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
Domanska, Marta K; Wrona, Dominik; Kasson, Peter M (2013) Multiphasic effects of cholesterol on influenza fusion kinetics reflect multiple mechanistic roles. Biophys J 105:1383-7
Kasson, Peter M; Hess, Berk; Lindahl, Erik (2013) Probing microscopic material properties inside simulated membranes through spatially resolved three-dimensional local pressure fields and surface tensions. Chem Phys Lipids 169:106-12
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