INTRODUCTION: It is well known that varicella zoster virus (VZV) infects and becomes latent in neurons in ganglia of the cranial nerves and dorsal roots and upon reactivation leads to zoster (shingles). However, there are also ganglia associated with the enteric nervous system (ENS). Reactivation of VZV within the ENS can infect gastrointestinal (GI) targets and cause enteric zoster.


DISCUSSION: Before the reactivation of VZV in the ENS was known, varicella zoster virus was associated with inflammatory bowel disease and perforated ulcers. Enteric zoster from reactivation of vaccine-type virus (vOka) has been found to cause perforating gastric ulcers. Because the neurons in the ENS convey active VZV to visceral and vascular targets, reactivation of VZV in autonomic neurons may cause serious disease of the vasculature, or viscera, without cutaneous manifestations. Gershon & Gershon describe the mechanism of VZV latency in the ENS1. They examined isolated guinea pig enteric neurons and detected late viral proteins, glycoproteins gE, gI, and gB, as well as immediate early proteins, including ORFs 29p, 62p and 63p which were all intranuclear. Evidence of reactivation included expression of late proteins, nuclear translocation of immunofluorescence of the immediate early proteins, production of electron microscopically visible virions, transmission of infection to co-cultured MeWo cells, and death of the neurons within 72 hours of the expression of ORF61. The burden of VZV-induced GI disease cannot yet be assessed, the researchers’ observations made using salivary VZV DNA as a noninvasive marker suggest that enteric zoster may be far more common than realized. They developed a guinea pig model of VZV latency and reactivation to learn how VZV establishes and maintains latency in enteric neurons, what provokes reactivation, and the manifestations of enteric zoster. Their observations suggest that immunosuppression, combined with corticotrophin releasing hormone, induces VZV to reactivate in guinea pigs. The resulting syndrome resembled disseminated zoster. The intravenous injection of VZVORF66.GFP-infected lymphocytes produced a latent infection in almost all dorsal root ganglia and enteric neurons. This was the first animal in which latent infection and reactivation of VZV was shown. Since then, simian varicella virus has also been found to establish latency in the monkey ENS (Ouwendijk et al2). The observation that VZV-infected CD3+ lymphocytes of guinea pigs and humans transmit latent infection to enteric neurons is significant.


CONCLUSION: The biological reason of how lymphocytes deliver only latent VZV to neurons, including those of the ENS, is unknown. Small reactivations of VZV in the bowel might be controllable because the gut is a major immune organ and might even help to maintain long-term immunity to varicella (postulated by Gershon&Gershon), however larger reactivation events can be devastating when is causes pseudoobstrution or perforating ulcers. The hidden nature of enteric zoster and its low index of suspicion have limited what is currently known about it. Their observations with salivary VZV DNA as a noninvasive marker suggest that enteric zoster may also be a common problem. The relationship of VZV and the recurrent zoster to those who have Crohn’s disease also merits further investigation. The guinea pig model of VZV latency and reactivation described here may help to determine how VZV establishes latency in the ENS, what provokes reactivation, the manifestations of enteric zoster, and ultimately, it’s contribution to GI disease.




  1. Gershon, M. and A. Gershon. (2018). Varicella-Zoster Virus and the Enteric Nervous System. J. Inf. Dis (suppl2). 218, S113. Https://
  2. Ouwendijk, W.J.D., van Veen S., Mehraban, T., Mahalingam R., Verjans G. M. (2018). Simian varicella virus infects enteric neurons and α4β7 integrin-expressing gut-tropic T-cells in nonhuman primates. Viruses 10(4) 156.

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