Varicella-Zoster Virus Pathogenesis and Immunobiology: New Concepts Emerging from Investigations with the SCIDhu Mouse Model
| Autor: | Charles Grose, Chia-Chi Ku, Jaya Besser, Ann M. Arvin, Allison Abendroth |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Herpesvirus 3
Human viruses T-Lymphocytes Immunology Genes MHC Class II Genes MHC Class I Mice Transgenic Mice SCID Biology medicine.disease_cause Virus Replication Microbiology Models Biological Herpesviridae Virus Mice Chickenpox Cell Movement Virology medicine Animals Humans Kinase activity Tropism Skin integumentary system Virulence Varicella zoster virus virus diseases biochemical phenomena metabolism and nutrition Acquired immune system eye diseases Immunity Innate Disease Models Animal Viral replication Virion assembly Insect Science Mutation Minireview Protein Kinases |
| Popis: | These experiments provide evidence in support of a critical role for T-cell tropism in VZV pathogenesis and suggest that the prolonged varicella incubation period represents the time required for VZV to overcome previously unrecognized potent innate antiviral responses, especially IFN-α production, mediated directly by epidermal cells. The initial phase of VZV pathogenesis appears to be facilitated by virus-mediated modulation of MHC-I and MHC-II expression and by the failure of VZV to trigger up-regulation of inflammatory adhesion molecules on capillary endothelial cells in skin. Eliminating ORF47 kinase activity impaired virion production and envelopment, which was associated with a dramatic reduction of VZV virulence in skin and a complete block of VZV infectivity for T cells in SCIDhu xenografts. Our interpretation of these observations is that VZV T-cell tropism is much more dependent on virion assembly than is VZV replication in epidermal cells. Some VZV infectivity is retained in skin if cell fusion functions are preserved, allowing cell-cell spread even when virion production and envelopment are impaired quite significantly. In contrast, VZV T-cell tropism appears to require efficient virion formation and egress for transfer to uninfected cells. Genetically engineered mutations in the VZV genome that result in the retention of some capacity to replicate in skin, at a level sufficient to elicit adaptive immunity to VZV, while eliminating infection of T cells by interfering with virion assembly may yield improved live attenuated VZV vaccines. |
| Databáze: | OpenAIRE |
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