Influenza A virus entry and membrane fusion

Influenza A virus membrane fusion and entry. Cartoon was adapted and modified from the review by Chlanda and Zimmerberg, 2016.

Influenza A virus (IAV) is a pleiomorphic, enveloped virus that enters the host cell either by endocytosis or macropinocytosis and fuses with the endosomal membrane in a Hemagglutinin (HA)-mediated process that occurs at low pH. Neither the structure of the HA fusion intermediates nor the spatial orientation of the post-fusion HA with respect to the fusion pore are known. We will use plasmid-derived IAV-like particles (VLPs), which are not infectious and unlike virus can carry HA with a mutation in the fusion peptide. The HA mediated membrane fusion pathway is sensitive to physical properties of the target membrane (i.e. elasticity and spontaneous curvature) and can be deviated into a dead-end product characterized by membrane rupture and the presence of arrested low-pH HA intermediates. We will use cryo-ET and subtomogram averaging to further characterize the structure of HA fusion intermediates. This will be critical to understand the mechanistic details of fusion and to identify ways to specifically interfere with this process. In addition, we will study viral fusion and disassembly in the cells close to their native state using cryo-CLEM, cryo-FIB/SEM and cryo-ET. This will allow to further investigate the role of host factors such as aggresome machinery, cytoskeleton, IFITMs proteins and lipids such as cholesterol on the membrane fusion and virion dissasembly.

 

Hemagglutinin interacting with liposomes at low pH (Chlanda P, et al, Nature Microbiology, 2016)
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