Latent and lytic infection of isolated guinea pig enteric ganglia by varicella zoster virus

Abstract

Varicella zoster virus (VZV) has been demonstrated to infect guinea pig enteric neurons in vitro. Latent infection of isolated enteric neurons is established when the cultures predominantly consist of neurons and they are exposed to cell-free VZV. Neurons harboring latent infection survive for weeks in vitro and express mRNA encoding ORFs 4, 21, 29, 40, 62, and 63, but not 14(gC) or 68 (gE) (although DNA encoding the glycoproteins is present). The expressed proteins are the same as those that are also expressed in human sensory neurons harboring latent VZV. In addition to mRNA, the immunoreactivities of ORFs 4, 21, 29, 62, and 63 can be detected. ORF 62 and 29 proteins are cytoplasmic and not intranuclear. VZV does not preferentially infect and/or become latent in intrinsic enteric primary afferent neurons indicating that the virus is latent in these neurons. Lytic infection occurs when mixed cultures of neurons and non-neuronal cells of the bowel wall are exposed to cell-free VZV or when isolated enteric neurons are exposed to cell-associated VZV. When lytic infection occurs, enteric neurons die within 48 hr. Prior to their death, neurons express VZV glycoproteins, including gE and gB, and ORF 62 and 29 proteins are intranuclear. This new animal model should facilitate studies of VZV latency and the efficacy of therapies designed to prevent VZV infection, latency, and reactivation.

Enteric Nervous System: Neuropathic Gastrointestinal Motility

“…On the other hand, the varicella-zoster virus (i.e., chickenpox) establishes latency in ENS neurons and can reactivate to lyse and kill the neurons within 48 h of infection [54,55,[67][68][69].…”

“…The identity of the three antigens and their localization in the protected environment of a neuronal nucleus prompt the question of how the immune system ever encounters them during the lifetime of an individual. An intriguing hypothetical answer is that activation of a latent viral infection leads to lysis and thereby exposure of the nuclear antigens to detection by the immune system, as is the case for varicella-zoster virus [54,55,[67][68][69].…”

Varicella-zoster virus infection of human neural cells in vivo

“…Herpes simplex virus 1 produces latency-associated antisense mRNA transcripts (LATs) in neuronal cell nuclei, and viral proteins are not detected in human autopsy specimens or animal models of persistent infection (6). In contrast, VZV has no LAT sequence, and transcription or translation of VZV genes encoding the IE major transactivating protein, IE62, the IE63 coregulatory protein, and ORFs 4, 21, 29, 40, and 66 has been reported in ganglia (2,4,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18).…”

Varicella zoster virus infection

“…However, surgery and the disorder that necessitated it are undoubtedly stressful; thus, these transcripts could reflect stress-induced gene expression rather than latency-associated transcription. Interestingly, the same genes (ORF4, ORF21, ORF29, ORF62, ORF63 and ORF66) are expressed during latency in guinea pig dorsal root ganglia and enteric neurons 39,[45][46][47] that were obtained without stress to the animals or post-mortem delay.…”

“…All latency-associated proteins are cytoplasmic, but become nuclear during productive infection [53][54][55] . Immediate early and early proteins are also cytoplasmic in latently infected guinea pig neurons and translocate to the nucleus when reactivation is induced 42,46,47,56 .…”