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Dissecting Host-virus Interaction in Lytic Replication of a Model Herpesvirus
Published on: October 7, 2011
Glycoprotein B cleavage is important for murid herpesvirus 4 to infect myeloid cells
Daniel L Glauser1, Ricardo Milho, Bruno Frederico
1Division of Virology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
Abstract:
Glycoprotein B (gB) is a conserved herpesvirus virion component implicated in membrane fusion. As with many-but not all-herpesviruses, the gB of murid herpesvirus 4 (MuHV-4) is cleaved into disulfide-linked subunits, apparently by furin. Preventing gB cleavage for some herpesviruses causes minor infection deficits in vitro, but what the cleavage contributes to host colonization has been unclear. To address this, we mutated the furin cleavage site (R-R-K-R) of the MuHV-4 gB. Abolishing gB cleavage did not affect its expression levels, glycosylation, or antigenic conformation. In vitro, mutant viruses entered fibroblasts and epithelial cells normally but had a significant entry deficit in myeloid cells such as macrophages and bone marrow-derived dendritic cells. The deficit in myeloid cells was not due to reduced virion binding or endocytosis, suggesting that gB cleavage promotes infection at a postendocytic entry step, presumably viral membrane fusion. In vivo, viruses lacking gB cleavage showed reduced lytic spread in the lungs. Alveolar epithelial cell infection was normal, but alveolar macrophage infection was significantly reduced. Normal long-term latency in lymphoid tissue was established nonetheless.
Insights
Herpesvirus Glycoprotein B cleavage by furin is crucial for efficient infection of myeloid cells. Preventing this cleavage impairs viral spread in the lungs but does not affect latency.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- Glycoprotein B (gB) is essential for herpesvirus entry into host cells.
- gB is proteolytically cleaved into subunits by host cell proteases like furin.
- The role of gB cleavage in herpesvirus pathogenesis and host colonization remains largely unknown.
Purpose of the Study:
- To investigate the functional significance of Glycoprotein B (gB) cleavage by furin in murid herpesvirus 4 (MuHV-4) infection.
- To determine the impact of impaired gB cleavage on viral entry, spread, and latency in vivo and in vitro.
Main Methods:
- Site-directed mutagenesis was used to abolish the furin cleavage site (R-R-K-R) in MuHV-4 gB.
- In vitro viral entry assays were performed using various cell types, including fibroblasts, epithelial cells, macrophages, and dendritic cells.
- In vivo studies assessed viral lytic spread in the lungs and latency establishment in lymphoid tissues.
Main Results:
- Abolishing the gB furin cleavage site did not affect gB expression, glycosylation, or conformation.
- Mutant viruses exhibited normal entry into fibroblasts and epithelial cells but a significant deficit in infecting myeloid cells (macrophages, dendritic cells).
- In vivo, viruses lacking gB cleavage showed reduced lytic spread in the lungs, specifically reduced alveolar macrophage infection, while latency was unaffected.
Conclusions:
- gB cleavage by furin is critical for efficient MuHV-4 entry into myeloid cells, likely at a post-endocytic fusion step.
- gB cleavage contributes to viral pathogenesis by promoting lytic spread in the lungs, particularly in macrophages.
- The cleavage of gB is not essential for establishing long-term latency in lymphoid tissues.
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