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Filovirus entry into cells - new insights.

ABSTRACT: Filoviruses are hemorrhagic fever-causing agents that produce enveloped virions with a filamentous morphology. The viral surface glycoprotein, GP, orchestrates the surprisingly complex process by which filoviruses gain access to the cytoplasm of their host cells. GP mediates viral attachment to cells through multiple, redundant interactions with cell-surface factors. GP then induces virion internalization by a process that resembles cellular macropinocytosis. Within the endo/lysosomal pathway, GP undergoes a series of structural rearrangements, controlled by interactions with host factors, that prime and activate it to bring about fusion between the viral and cellular lipid bilayers. Membrane fusion delivers the viral nucleocapsid core into the cytoplasm, which is the site of filovirus replication. This review summarizes our understanding of the filovirus entry mechanism, with emphasis on recent findings.

SUBMITTER: Miller EH

PROVIDER: S-EPMC3322298 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Filovirus entry into cells - new insights.

Miller Emily Happy EH Chandran Kartik K

Current opinion in virology 20120323 2

Filoviruses are hemorrhagic fever-causing agents that produce enveloped virions with a filamentous morphology. The viral surface glycoprotein, GP, orchestrates the surprisingly complex process by which filoviruses gain access to the cytoplasm of their host cells. GP mediates viral attachment to cells through multiple, redundant interactions with cell-surface factors. GP then induces virion internalization by a process that resembles cellular macropinocytosis. Within the endo/lysosomal pathway, G ...[more]

PMID: 22445965

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Project description:Ebolavirus (EBOV) and Marburgvirus (MARV) that compose the filovirus family of negative strand RNA viruses infect a broad range of mammalian cells. Recent studies indicate that cellular entry of this family of viruses requires a series of cellular protein interactions and molecular mechanisms, some of which are unique to filoviruses and others are commonly used by all viral glycoproteins. Details of this entry pathway are highlighted here. Virus entry into cells is initiated by the interaction of the viral glycoprotein(1) subunit (GP(1)) with both adherence factors and one or more receptors on the surface of host cells. On epithelial cells, we recently demonstrated that TIM-1 serves as a receptor for this family of viruses, but the cell surface receptors in other cell types remain unidentified. Upon receptor binding, the virus is internalized into endosomes primarily via macropinocytosis, but perhaps by other mechanisms as well. Within the acidified endosome, the heavily glycosylated GP(1) is cleaved to a smaller form by the low pH-dependent cellular proteases Cathepsin L and B, exposing residues in the receptor binding site (RBS). Details of the molecular events following cathepsin-dependent trimming of GP(1) are currently incomplete; however, the processed GP(1) specifically interacts with endosomal/lysosomal membranes that contain the Niemann Pick C1 (NPC1) protein and expression of NPC1 is required for productive infection, suggesting that GP/NPC1 interactions may be an important late step in the entry process. Additional events such as further GP(1) processing and/or reducing events may also be required to generate a fusion-ready form of the glycoprotein. Once this has been achieved, sequences in the filovirus GP(2) subunit mediate viral/cellular membrane fusion via mechanisms similar to those previously described for other enveloped viruses. This multi-step entry pathway highlights the complex and highly orchestrated path of internalization and fusion that appears unique for filoviruses.

Dataset Information

Filovirus entry into cells - new insights.

Publications

Filovirus entry into cells - new insights.

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