title: Varicella-zoster virus infection induces autophagy in both cultured cells and human skin vesicles.
abstract: When grown in cultured cells, varicella-zoster virus (VZV) forms many aberrant light particles and produces low titers. Various studies have explored the reasons for such a phenotype and have pointed to impaired expression of specific late genes and at lysosomal targeting of egressing virions as possible causes. In the studies presented here, we report that the autophagic degradation pathway was induced at late time points after VZV infection of cultured cells, as documented by immunoblot analysis of the cellular proteins LC3B and p62/SQSTM1, along with electron microscopy analysis, which demonstrated the presence of both early autophagosomes and late autophagic compartments. Autophagy was induced in infected cells even in the presence of phosphonoacetic acid, an inhibitor of viral late gene expression, thus suggesting that accumulation of immediate-early and early viral gene products might be the major stimulus for its induction. We also showed that the autophagic response was not dependent on a specific cell substrate, virus strain, or type of inoculum. Finally, using immunofluorescence imaging, we demonstrated autophagosome-specific staining in human zoster vesicles but not in normal skin. Thus, our results document that this innate immune response pathway is a component of the VZV infectious cycle in both cultured cells and the human skin vesicle, the final site of virion formation in the infected human host.
authors.affiliation: Global Vaccines Technology and Engineering-Bioanalytics, Merck Manufacturing Division, Merck & Co, Inc, West Point, Pennsylvania 19486, USA.
authors.forename: Marie-Noëlle
authors.initials: MN
authors.lastname: Takahashi
authors.forename: Wallen
authors.initials: W
authors.lastname: Jackson
authors.forename: Donna T
authors.initials: DT
authors.lastname: Laird
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Culp
authors.forename: Charles
authors.initials: C
authors.lastname: Grose
authors.forename: John I
authors.initials: JI
authors.lastname: Haynes
authors.forename: Luca
authors.initials: L
authors.lastname: Benetti
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy; D001706:Biopsy; D002460:Cell Line; D002474:Cell-Free System; D002644:Chickenpox / Q000473:pathology* / Q000821:virology*; D003593:Cytoplasm / Q000378:metabolism; D015967:Gene Expression Regulation, Viral; D014645:Herpesvirus 3, Human / Q000502:physiology*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D000071456:Sequestosome-1 Protein; D012871:Skin Diseases / Q000473:pathology* / Q000821:virology*; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014759:Viral Envelope Proteins