20962081
not annotated - annotated - LINNAEUS only
Varicella-zoster virus glycoprotein E is a critical determinant of virulence in the SCID mouse-human model of neuropathogenesis.
Varicella-zoster virus (VZV) is a neurotropic alphaherpesvirus. VZV infection of human dorsal root ganglion (DRG) xenografts in immunodeficient mice models the infection of sensory ganglia. We examined DRG infection with recombinant VZV (recombinant Oka [rOka]) and the following gE mutants: gEDelta27-90, gEDeltaCys, gE-AYRV, and gE-SSTT. gEDelta27-90, which lacks the gE domain that interacts with a putative receptor insulin-degrading enzyme (IDE), replicated as extensively as rOka, producing infectious virions and significant cytopathic effects within 14 days of inoculation. Since neural cells express IDE, the gE/IDE interaction was dispensable for VZV neurotropism. In contrast, gEDeltaCys, which lacks gE/gI heterodimer formation, was significantly impaired at early times postinfection; viral genome copy numbers increased slowly, and infectious virus production was not detected until day 28. Delayed replication was associated with impaired cell-cell spread in ganglia, similar to the phenotype of a gI deletion mutant (rOkaDeltagI). However, at later time points, infection of satellite cells and other supportive nonneuronal cells resulted in extensive DRG tissue damage and cell loss such that cytopathic changes observed at day 70 were more severe than those for rOka-infected DRG. The replication of gE-AYRV, which is impaired for trans-Golgi network (TGN) localization, and the replication of gE-SSTT, which contains mutations in an acidic cluster, were equivalent to that of rOka, causing significant cytopathic effects and infectious virus production by day 14; genome copy numbers were equivalent to those of rOka. These experiments suggest that the gE interaction with cellular IDE, gE targeting to TGN sites of virion envelopment, and phosphorylation at SSTT are dispensable for VZV DRG infection, whereas the gE/gI interaction is critical for VZV neurovirulence.
Ann file
T1 Species 0 22 Varicella-zoster virus
N1 Reference T1 Taxonomy:10335
T2 Species 95 100 human
N2 Reference T2 Taxonomy:9606
T3 Species 131 153 Varicella-zoster virus
N3 Reference T3 Taxonomy:10335
T4 Species 155 158 VZV
N4 Reference T4 Taxonomy:10335
T5 Species 195 198 VZV
N5 Reference T5 Taxonomy:10335
T6 Species 212 217 human
N6 Reference T6 Taxonomy:9606
T7 Species 364 367 VZV
N7 Reference T7 Taxonomy:10335
T8 Species 788 791 VZV
N8 Reference T8 Taxonomy:10385
T9 Species 1934 1937 VZV
N9 Reference T9 Taxonomy:10385
T10 Species 89 94 mouse
T11 Species 275 279 mice
N10 Reference T11 Taxonomy:10090 Mus musculus
T12 Species 1999 2002 VZV
N11 Reference T12 Taxonomy:10335