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Saving varicella from suicide

Intact VZV is released when trafficking to late endosomes is shut off in skin. GERSHON/ELSEVIER

Varicella zoster virus (VZV) causes both varicella (chickenpox) and zoster (shingles). VZV spreads throughout the body, but it does so slowly, and virus only emerges extracellularly in the skin where it can spread to other hosts. That behavior is now explained by Zhenglun Zhu (Harvard Medical School, Boston, MA), Jason Chen, Anne Gershon, and Michael Gershon (Columbia University, New York, NY). They show that in most tissues VZV is diverted to late endosomes for destruction, but in the most superficial epidermal cells that cellular trafficking pathway is turned off, resulting in secretion of VZV.

Trafficking from the Golgi system to the late endosome is mediated by the cation-independent mannose 6-phosphate receptor (MPR^ci). MPR^ci has been implicated in both VZV entry (mannose 6-phosphate can block infection by free virus) and viral sorting (mature virus ends up in late endosomes). "The idea was around, based on indirect evidence, but it needed to be shown," says Michael Gershon.

The team tested the theory of MPR^ci involvement by getting rid of MPR^ci with antisense and siRNA. The resulting cells could not be infected with cell-free virus. But if infected by other means they did not send mature virus to late endosomes for destruction but instead secreted intact virus. The latter phenotype was mimicked in the outer skin layer of biopsies from patients, which showed no MPR^ci expression and high virus secretion.

Thus VZV uses the MPR^ci as a coreceptor for entry, and then uses it to direct intracellular mature virus particles to the degradative late endosome. This slows viral proliferation and prevents host death: the only remaining viral particles are immature nucleocapsids that spread via slow cell fusion events.

The skin is a different proposition. MPR^ci and lysosomal sorting are turned off as the outermost skin cells devote their last living hours to the secretion of waterproofing ceramides. The VZV particles follow the remaining trafficking pathway—constitutive secretion to the cell surface—where they are released as infectious virions. The cell-free virus can then either infect and establish latency in exposed sensory nerves or spread to other hosts.

Reference:

Chen, J.J., et al. 2004. Cell. 119:915–926.[CrossRef][Medline]

William A. Wells

wellsw{at}rockefeller.edu

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This Article Full Text (PDF, 426K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wells, W. A. Search for Related Content PubMed Articles by Wells, W. A. Social Bookmarking                            What's this?