Abstract
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 glycoprotein1 subunit (GP1) 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 GP1 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 GP1 are currently incomplete; however, the processed GP1 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 GP1 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 GP2 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.
Highlights
Filoviruses (family Mononegavirales, genera Ebolavirus (EBOV) and Marburgvirus (MARV)) are single-stranded, negative-sense RNA viruses that exhibit a unique heterogeneous filamentous structure
While furin processing of the filovirus GP routinely occurs within the Golgi apparatus before the glycoprotein is expressed on the plasma membrane, proteolytic clipping is not required for virion infectivity [4]
In panel C, the base domain of glycoprotein1 subunit (GP1) that interacts with GP2 is shown in royal blue, the head domain is shown in teal with the beta-strands and adjacent loop region containing the receptor binding site (RBS) highlighted in red and the glycan cap is shown in gold
Summary
Filoviruses (family Mononegavirales, genera Ebolavirus (EBOV) and Marburgvirus (MARV)) are single-stranded, negative-sense RNA viruses that exhibit a unique heterogeneous filamentous structure. Both EBOV and MARV infect a wide variety of mammals and this wide tropism has complicated the identification of cellular proteins required for viral entry. No therapeutic drugs or vaccines are currently available to treat or prevent filoviral infection. Because of this and the high lethality associated with infection, filoviruses are considered Category A Priority Pathogens by NIAID and, in recent years, much research has focused on understanding how these viruses bind to and enter permissive cells
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