BPS2026 – Plasma membrane serves as a restriction factor for influenza fusion and entry

Enveloped viruses infect via a process of membrane fusion, typically to either the plasma membrane or a specific stage of the endocytic pathway. Influenza virus is a good model system for membrane specificity because it normally fuses in mid-late endosomes but can be exogenously induced to fuse at the plasma membrane. We show that influenza-forced fusion at the plasma membrane is much less-efficient at causing infection than native endocytic fusion and that most of this effect can be attributed to a difference in fusion permissiveness between the two membranes. Fusion to the plasma membrane is not trivially rescued by supplementing membranes with the endosome-enriched lipid BMP, but infection at the plasma membrane can be greatly enhanced by depleting cholesterol. This result suggests that cholesterol-dependent plasma membrane organization and/or trafficking are critical to restricting influenza viral entry. It also raises the question of how viruses adapt to their physiological membrane niches.