Trafficking from the Golgi system to the late endosome is mediated by the cation-independent mannose 6-phosphate receptor (MPRci). MPRci 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 MPRci involvement by getting rid of MPRci 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 MPRci expression and high virus secretion.
Thus VZV uses the MPRci 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. MPRci 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.