Varicella-Zoster Virus-Infected Human Sensory Neurons Are Resistant to Apoptosis, yet Human Foreskin Fibroblasts Are Susceptible: Evidence for a Cell-Type-Specific Apoptotic Response

Abstract

The induction of apoptosis or programmed cell death in virus-infected cells is an important antiviral defense mechanism of the host, and some herpesviruses have evolved strategies to modulate apoptosis in order to enhance their survival and spread. In this study, we examined the ability of varicella-zoster virus (VZV) to induce apoptosis in primary human dorsal root ganglion neurons and primary human foreskin fibroblasts (HFFs). Three independent methods (annexin V, TUNEL [terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling] staining, and electron microscopy) were used to assess apoptosis in these cells on days 1, 2, and 4 postinoculation. By all three methods, apoptosis was readily detected in VZV-infected HFFs. In stark contrast, apoptosis was not detected during productive VZV infection of neurons. The low-passage clinical isolate Schenke and the tissue culture-adapted ROka strain both induced apoptosis in HFFs but not in neurons, suggesting that this cell-type-specific apoptotic phenotype was not VZV strain specific. These data show that the regulation of apoptosis differs markedly between HFFs and neurons during productive VZV infection. Inhibition of apoptosis during infection of neurons may play a significant role in the establishment, maintenance, and reactivation of latent infection by promoting survival of these postmitotic cells.

Bovine Herpesvirus 4 Induces Apoptosis of Human Carcinoma Cell Lines In vitro and In vivo

“…shown for other herpesviruses (40,41). Recently, Hood et al (41) provided evidence for a cell type-specific apoptotic response to VZV infection.…”

“…Recently, Hood et al (41) provided evidence for a cell type-specific apoptotic response to VZV infection. They postulated that viral interference with apoptotic pathways is different at the different stages of the infection.…”

Varicella-Zoster Virus ORF63 Inhibits Apoptosis of Primary Human Neurons

“…It has been proposed that the pain associated with herpes zoster and postherpetic neuralgia is due to neural tissue destruction caused by VZV reactivation (35,36). However, we recently reported that VZV-infected neurons, but not VZV-infected human fibroblasts (HF), were resistant to apoptosis (20), suggesting that neuronal destruction in vivo may be a corollary of the host cell immune response. This neuron-specific antiapoptotic function could increase the ability of VZV to efficiently establish latency and allow augmented virion production for axonal transport to the skin and reactivation as zoster lesions.…”

“…Human fetal spines (14 to 20 weeks of gestation) were obtained after informed consent and approval by the University of Sydney Human Ethics Committee. DRG were dissected from the spine, dissociated, and cultured as previously described (20). Dissociated neuronal cultures were seeded to give a range of 200 to 500 neurons per well.…”

Aberrant Virion Assembly and Limited Glycoprotein C Production in Varicella-Zoster Virus-Infected Neurons

“…While both neurons and nonneuronal cells became infected, productive infection of nonneuronal cells resulted in destruction of the entire culture (2,3). Later studies in which VZV-infected human fetal fibroblasts were cocultivated with explanted human fetal dorsal root ganglia indicated that neurons were resistant to apoptosis (4). Recently, heterogeneous cultures derived from human embryonic stem cells that contained neurons were infected with VZV, but again productive infection ensued, presumably due to the presence of a significant proportion of nonneuronal cells (5).…”