VZV infection of keratinocytes: production of cell-free infectious virions in vivo.
Varicella-zoster virus (VZV) is the cause of varicella (chickenpox) and zoster (shingles). Varicella is a primary infection that spreads rapidly in epidemics while zoster is a secondary infection that occurs sporadically as a result of the reactivation of previously acquired VZV. Reactivation is made possible by the establishment of latency during the initial episode of varicella. The signature lesions of both varicella and zoster are cutaneous vesicles, which are filled with a clear fluid that is rich in infectious viral particles. It has been postulated that the skin is the critical organ in which both host-to-host transmission of VZV and the infection of neurons to establish latency occur. This hypothesis is built on evidence that the large cation-independent mannose 6-phosphate receptor (MPR(ci)) interacts with VZV in virtually all infected cells, except those of the suprabasal epidermis, in a way that prevents the release of infectious viral particles. Specifically, the virus is diverted in an MPR(ci)-dependent manner from the secretory pathway to late endosomes where VZV is degraded. Because nonepidermal cells are thus prevented from releasing infectious VZV, a slow process, possibly involving fusion of infected cells with their neighbors, becomes the means by which VZV is disseminated. In the epidermis, however, the maturation of keratinocytes to give rise to corneocytes in the suprabasal epidermis is associated uniquely with a downregulation of the MPR(ci). As a result, the diversion of VZV to late endosomes does not occur in the suprabasal epidermis where vesicular lesions occur. The formation of the waterproof, chemically resistant barrier of the epidermis, however, requires that constitutive secretion outlast the downregulation of the endosomal pathway. Infectious VZV is therefore secreted by default, accounting for the presence of infectious virions in vesicular fluid. Sloughing of corneocytes, aided by scratching, then aerosolizes the virus, which can float with dust to be inhaled by susceptible hosts. Infectious virions also bathe the terminals of those sensory neurons that innervate the epidermis. These terminals become infected with VZV and provide a route, retrograde transport, which can conduct VZV to cranial nerve (CNG), dorsal root ganglia (DRG), and enteric ganglia (EG) to establish latency. Reactivation returns VZV to the skin, now via anterograde transport in axons, to cause the lesions of zoster. Evidence in support of these hypotheses includes observations of the VZV-infected human epidermis and studies of guinea pig neurons in an in vitro model system.
Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. mdg4@columbia.edu
Michael D
MD
Gershon
Anne A
AA
Gershon
D000818:Animals; D002644:Chickenpox / Q000276:immunology / Q000821:virology*; D006562:Herpes Zoster / Q000276:immunology / Q000821:virology*; D014645:Herpesvirus 3, Human / Q000276:immunology / Q000648:ultrastructure; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D015603:Keratinocytes / Q000821:virology*; D014771:Virion / Q000276:immunology; D017735:Virus Latency; D014779:Virus Replication