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: gEΔ27-90, gEΔCys, gE-AYRV, and gE-SSTT. gEΔ27-90, 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, gEΔCys, 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 (rOkaΔgI). 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.
Department of Pediatrics, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305, USA. zerboni@stanford.edu
Leigh
L
Zerboni
Barbara
B
Berarducci
Jaya
J
Rajamani
Carol D
CD
Jones
James L
JL
Zehnder
Ann
A
Arvin
D000818:Animals; D002460:Cell Line; D017950:Ganglia, Sensory / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D006562:Herpes Zoster / Q000473:pathology* / Q000821:virology; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000821:virology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000378:metabolism*; D014774:Virulence; D053586:Virus Internalization; D014779:Virus Replication
D014759:Viral Envelope Proteins; C056913:glycoprotein E, varicella-zoster virus