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Multiphasic effects of cholesterol on influenza fusion kinetics reflect multiple mechanistic roles.

ABSTRACT: The envelope lipid composition of influenza virus differs from that of the cellular plasma membrane from which it buds. Viruses also appear to fuse preferentially to specific membrane compartments, suggesting that the lipid environment may influence permissiveness for fusion. Here, we investigated the influence of the membrane environment on fusion, focusing on cholesterol composition. Strikingly, manipulating cholesterol levels in the viral membrane had different effects on fusion kinetics compared with analogous changes to the target membrane. Increasing cholesterol content in target vesicles increased lipid- and contents-mixing rates. Moderate cholesterol depletion from the viral membrane sped fusion rates, whereas severe depletion slowed the process. The pleiotropic effects of cholesterol include alterations in both membrane-bending moduli and lateral organization. Because influenza virions have demonstrated cholesterol-dependent lateral organization, to separate these effects, we deliberately selected a target vesicle composition that does not support lateral heterogeneity. We therefore postulate that the monotonic response of fusion kinetics to target membrane cholesterol reflects bending and curvature effects, whereas the multiphasic response to viral cholesterol levels reflects the combined effects of lateral organization and material properties.

SUBMITTER: Domanska MK

PROVIDER: S-EPMC3785876 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Multiphasic effects of cholesterol on influenza fusion kinetics reflect multiple mechanistic roles.

Domanska Marta K MK Wrona Dominik D Kasson Peter M PM

Biophysical journal 20130901 6

The envelope lipid composition of influenza virus differs from that of the cellular plasma membrane from which it buds. Viruses also appear to fuse preferentially to specific membrane compartments, suggesting that the lipid environment may influence permissiveness for fusion. Here, we investigated the influence of the membrane environment on fusion, focusing on cholesterol composition. Strikingly, manipulating cholesterol levels in the viral membrane had different effects on fusion kinetics comp ...[more]

PMID: 24047989

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Project description:Cholesterol has been implicated in various viral life cycle steps for different enveloped viruses, including viral entry into host cells, cell-cell fusion, and viral budding from infected cells. Enveloped viruses acquire their membranes from their host cells. Although cholesterol has been associated with the binding and entry of various enveloped viruses into cells, cholesterol's exact function in the viral-cell membrane fusion process remains largely elusive, particularly for the paramyxoviruses. Furthermore, paramyxoviral fusion occurs at the host cell membrane and is essential for both virus entry (virus-cell fusion) and syncytium formation (cell-cell fusion), central to viral pathogenicity. Nipah virus (NiV) is a deadly member of the Paramyxoviridae family, which also includes Hendra, measles, mumps, human parainfluenza, and various veterinary viruses. The zoonotic NiV causes severe encephalitis, vasculopathy, and respiratory symptoms, leading to a high mortality rate in humans. We used NiV as a model to study the role of membrane cholesterol in paramyxoviral membrane fusion. We used a combination of methyl-beta cyclodextrin (MβCD), lovastatin, and cholesterol to deplete or enrich cell membrane cholesterol outside cytotoxic concentrations. We found that the levels of cellular membrane cholesterol directly correlated with the levels of cell-cell fusion induced. These phenotypes were paralleled using NiV/vesicular stomatitis virus (VSV)-pseudotyped viral infection assays. Remarkably, our mechanistic studies revealed that cholesterol reduces an early F-triggering step but enhances a late fusion pore formation step in the NiV membrane fusion cascade. Thus, our results expand our mechanistic understanding of the paramyxoviral/henipaviral entry and cell-cell fusion processes.IMPORTANCE Cholesterol has been implicated in various steps of the viral life cycle for different enveloped viruses. Nipah virus (NiV) is a highly pathogenic enveloped virus in the Henipavirus genus within the Paramyxoviridae family, capable of causing a high mortality rate in humans and high morbidity in domestic and agriculturally important animals. The role of cholesterol for NiV or the henipaviruses is unknown. Here, we show that the levels of cholesterol influence the levels of NiV-induced cell-cell membrane fusion during syncytium formation and virus-cell membrane fusion during viral entry. Furthermore, the specific role of cholesterol in membrane fusion is not well defined for the paramyxoviruses. We show that the levels of cholesterol affect an early F-triggering step and a late fusion pore formation step during the membrane fusion cascade. Thus, our results expand our mechanistic understanding of the viral entry and cell-cell fusion processes, which may aid the development of antivirals.

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Multiphasic effects of cholesterol on influenza fusion kinetics reflect multiple mechanistic roles.

Publications

Multiphasic effects of cholesterol on influenza fusion kinetics reflect multiple mechanistic roles.

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