Varicella zoster virus (VZV), the cause of varicella (chickenpox) and zoster (shingles), is highly infectious but, paradoxically, spreads only by cell-to-cell contact in vitro. Cultured cells do not release infectious virions, because newly enveloped VZV is degraded in the acidic interiors of late endosomes. Evidence suggests that VZV is sorted to late endosomes because it follows the itinerary of mannose 6-phosphate receptors (MPRs); this pathway is followed because VZV is enveloped by MPR-containing cisternae of the trans-Golgi network (TGN). Viral glycoproteins (gps) segregate from cellular proteins within the membranes of these sacs, so that opposite faces form (i) an inner envelope that packages tegument and a nucleocapsid and (ii) an outer MPR-containing vesicle to transport the newly enveloped virions. This segregation is dependent upon the C-terminal region of gI. When gI, or its C-terminal, are deleted, the whole circumference of enveloping TGN sacs contains gps and an adherent coating of tegument (including ORF lOp) on their cytosolic surfaces. Adjacent cisternae adhere and envelopment fails. For VZV to be enveloped in the TGN, gps and tegument proteins must be targeted there. Some gps ('navigators""""""""), eg: gE and gI, contain TGN targeting signals in their primary sequence, while others, eg: gH and gL (""""""""passengers""""""""), concentrate in the TGN because they interact with """"""""navigators."""""""" Tegument may bind to gp endodomains; for example, co-expressed gE targets ORFIOp to the TGN. We now propose to identify gI domain(s) that are responsible for segregating cellular and viral gps/tegument in TGN cisternae. We will determine how the interplay of the TGN targeting and endocytosis signals of gI and gE assures that enough of each be delivered to the TGN and simultaneously retained at the cell surface (for purposes other than envelopment). We will investigate the relative roles in the internalization of gI, gE and the gE:gI complex played by caveolae and clathrin-coated pits. We will determine if gK contains a TGN targeting signal, or whether gK and gC are sorted to the TGN in complexes with """"""""navigators."""""""" We will test hypotheses that VZV entry into target cells and delivery to the TGN, are both MPR-dependent. For this purpose, we generated a human cell line that lacks MPRs. Infection, latency and their MPR-dependence in neurons will be investigated in guinea pig enteric ganglia. We have demonstrated that VZV infects enteric neurons in isolated ganglia and becomes latent or lytic depending upon the infection conditions.
| Gershon, Anne A; Gershon, Michael D (2010) Perspectives on vaccines against varicella-zoster virus infections. Curr Top Microbiol Immunol 342:359-72 |
| Gershon, Michael D; Gershon, Anne A (2010) VZV infection of keratinocytes: production of cell-free infectious virions in vivo. Curr Top Microbiol Immunol 342:173-88 |
