Why we care
Influenza virus has had a tremendous impact on the health of the countries where we work. The 1918-1918 flu pandemic caused the single greatest dip in life expectance in the United States during the 20th century, and also the single greatest number of annual deaths in Sweden. In addition to the threat of another severe pandemic from influenza, emerging viruses such as Zika pose a massive global health threat. We wish to understand the mechanistic basis for viral entry to help guide the development of better therapies for these pathogens.
Influenza virus infects cells via a process of membrane fusion. In addition to studying the biophysics of membrane fusion in simplified model systems, we seek to understand how physical mechanisms of fusion operate in the physiological context of infection. In particular, we are interested in 1) analyzing the critical mechanistic factors controlling fusion and 2) identifying how those factors can be manipulated either for antiviral therapies or biotechnological uses.
Membrane fusion is the primary means by which large molecular payloads are transported into cells. As such, membrane fusion provides the mechanism for the entry and infection by enveloped viruses such as influenza, Ebola, SARS, and HIV. Not surprisingly, the steps driving membrane fusion are the targets by which these critically important processes are regulated, and thus a fundamental understanding of membrane fusion mechanisms will enable the design of novel anti-viral drugs. When faced with the potential for rapidly emerging and highly virulent infections, such an understanding of fusion becomes of particular importance to both fundamental biology and national health.
What we do
We study several aspects of viral entry: how membrane composition can alter the mechanism and efficiency of entry, and how protein-lipid interactions mediate membrane fusion and release of the viral genome inside the cell. In each of these areas, we use a variety of biophysical, structural, and computational approaches to build an integrated understanding of viral entry.
Experimental study of fusion mechanisms is challenging because the transient events of fusion itself are preceded by slow activation steps. To help solve this quandary, we employ molecular dynamics simulations to generate physically-based models for lipid reorganization in fusion and the protein-lipid interactions by which both cells and invading viruses control the fusion process. Our lab also performs biophysical experiments on membrane fusion. By combining computational and experimental approaches under one roof, we hope to construct detailed integrated models for membrane fusion mechanism.
The primary means of immunity against viruses such as influenza as well as most emerging viruses (SARS-CoV-2, Zika, and others) is neutralizing antibodies. We study how antibodies interfere with infection. In particular, we develop technology to assess mechanisms of antibody neutralization and how this can be used to guide vaccine design.