# VZV in the enteric nervous system: pathogenesis and consequences

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $360,702

## Abstract

Summary
 Varicella zoster virus (VZV) famously establishes latency in dorsal root (DRG) and cranial nerve (CNG)
ganglia after its disseminated primary infection (varicella; chickenpox). VZV can reactivate from latency to
cause a localized secondary infection (zoster; shingles). VZV latency, however, is not restricted to
DRG/CNG; latent VZV is present in the enteric nervous system (ENS) in virtually everyone who has
experienced varicella or received the live attenuated varicella vaccine. VZV reactivates in the ENS (enteric
zoster) as it does in DRG/CNG but because enteric neurons lack cutaneous projections, enteric zoster occurs
without rash and may be an unsuspected cause of GI disease. A major hindrance to research on VZV has
been the absence of a suitable animal model. To overcome this difficulty, we demonstrated that VZV infects,
establishes latency, and reactivates in isolated guinea pig enteric neurons; moreover, VZV infects guinea
pigs in vivo, establishes latent infection in their DRG/CNG and ENS, and can be reactivated to produce a
secondary infection resembling disseminated zoster. VZV can be transported to the ENS from infected
epidermis in axons of DRG neurons that project both to the skin and gut but intravenous injection of VZV-
infected T lymphocytes establishes latency in almost every ENS and DRG neuron of the animal. It had been
thought that latent infection of enteric neurons could be established by cell-free VZV (VZVCF) but not by cell
associated VZV (VZVCA). VZV-infected lymphocytes, however, do not secrete VZVCF but they are able
transmit infection to neurons in vitro and in vivo that is exclusively latent. Aim 1 tests hypotheses that: (i)
evanescent cell fusion is responsible for transmission of VZV from lymphocytes to neurons; (ii) exosomes
derived from VZV-infected lymphocytes introduce stimulator of interferon genes (STING) to neurons; (iii)
STING induces a type1 interferon response in neurons that inhibits VZV proliferation and facilitates
establishment of latency. Aim 2 tests hypotheses that: (i) VZV-infected lymphocytes can induce a varicella-
like primary infection in guinea pigs if immunosuppression and stress precedes infection; (ii) restriction of
VZV latency allows localized reactivations to be confined to gut or skin; (iii) continuous activation of a
receptor tyrosine kinase transduction pathway, similar to that in HSV1 reactivation in sympathetic neurons,
regulates latent VZV genomes in enteric neurons. Aim 3 directly tests the hypothesis that salivary VZV DNA
in patients with unexplained abdominal pain severe enough to warrant endoscopy and biopsy is a marker of
enteric zoster. To validate this idea with a tissue diagnosis, we will analyze VZV DNA in saliva and GI
mucosal expression of gE transcripts and protein which would indicate productive VZV infection (enteric
zoster) in the bowel. This research makes the first use a novel animal model in which VZV reactivates in vivo
and the first application of a non-inv...

## Key facts

- **NIH application ID:** 9878097
- **Project number:** 5R01DK093094-08
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MICHAEL D GERSHON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,702
- **Award type:** 5
- **Project period:** 2011-08-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878097

## Citation

> US National Institutes of Health, RePORTER application 9878097, VZV in the enteric nervous system: pathogenesis and consequences (5R01DK093094-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9878097. Licensed CC0.

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