INFLUENZA FUSION

Understanding the effects of influenza hemagglutinin mutations on viral membrane fusion

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 Obiettivo del progetto (Objective)

Membrane fusion is a critical step in cellular entry and infection by enveloped viruses such as influenza. Influenza hemagglutinin catalyzes fusion by interacting with membrane lipids, but the nature of this interaction is not well understood. Experimental mutagenesis has yielded much data on the functional requirements of the proteins that catalyze fusion, but we have no robust theory that could have predicted these results. Developing a drug that inhibits viral entry has long been a goal, but high-affinity inhibitors have been challenging due in part to a lack of knowledge regarding important structural intermediates in viral membrane fusion. This proposal aims to aid target identification by developing robust mechanistic models of influenza viral entry.

This structural information has previously been challenging for both experimental and computational methods. Traditional crystallographic methods are hampered by the dynamic processes involved and the intimate involvement of the membrane environment. We have developed new computational methods and platforms that allow the simulation of large membrane assemblies on the timescales required to examine fusion mechanisms. We will simulate fusion both by native influenza hemagglutinin and by a series of mutants, matching these simulations against the results of cell-fusion assays. This approach will allows us to predict fusion protein structures and dynamics at high resolution while validating our simulations against experimental data. Using this combined approach, we hope to shed light on influenza fusion mechanisms and elucidate future antiviral drug targets.

Introduzione (Teaser)

The flu, is an infectious disease caused by influenza viruses (IVs). These can multiply only inside living cells and their fusion with the cell membrane is a critical step in entry and infection.

Descrizione progetto (Article)

Glycoprotein hemagglutinin (HA) on the membrane (envelope) of the virus binds sugars on the surfaces of epithelial cells in the nose, throat, and lungs of mammals, and intestines of birds. HA regulates fusion by interacting with membrane lipids, but the nature of this interaction is not well understood.

Developing a drug that inhibits viral entry is an important goal. The EU-funded 'Understanding the effects of influenza hemagglutinin mutations on viral membrane fusion' (INFLUENZA FUSION) three-year proposal aims to identify targets by developing mechanistic models of how the IV enters the cell.

Lipid tail protrusion is an uncommon event when the tails of the lipid molecules point out away from the interior of the lipid bilayer and is important for fusion. The researchers found that influenza mutants for tail protrusion were unable to cause membrane fusion in vivo and were also less potent inducers of lipid tail protrusions. Results of this work were published in high-impact journal.

The next stage forthe project includes study of the insertion of fusion peptides in the lipid bilayer. This is an ongoing initiative that will finish at the end of 2014 and researchers are continuing to investigate other viruses included in the study for the development of the model of the fusion.

INFLUENZA FUSION has the potential to aid in prediction of fusion protein structures and dynamics. Using this combined approach, researchers hope to shed light on IVs fusion mechanisms and elucidate future antiviral drug targets.