# VZV in the enteric nervous system: pathogenesis and consequences

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $575,787

## Abstract

ABSTRACT
 Varicella zoster virus (VZV) is so well known as the cause of cutaneous varicella (chickenpox) and
zoster (shingles) that it can be hard to imagine it as an enteric pathogen. VZV establishes latency during
varicella and returns to the skin in zoster when the neurons in which VZV reactivates have cutaneous
projections. Because a viremia occurs during varicella, VZV also infects and establishes latency in enteric
neurons that do not innervate the skin. VZV can reactivate in enteric neurons to give rise to “enteric zoster”,
which can occur without an associated rash. Because a rash may thus be absent, pain due to enteric zoster
can be occult. We have found, however, that VZV DNA, which is absent from normal saliva, is detectable in
saliva whenever an active (lytic) VZV infection is present in the body; thus, detection of salivary VZV is a non-
invasive diagnostic tool that, in combination with enteric signs and symptoms, helps to identify GI disorders
that involve VZV. We have found VZV transcripts and protein in endoscopic biopsies from patients with occult
abdominal pain and salivary VZV DNA, which verifies that these patients have enteric zoster. These
observations led us to investigate the potential association between VZV and achalasia in 15 patients. We
found salivary VZV DNA in 12/15 subjects examined prior to myotomy and, subsequently, VZV transcripts in
13/15 of the resected myotomy specimens. The tissue also contained VZV-immunoreactive (gE, gH, ORF40p)
neurons, nerve fibers, and multinucleated giant cells. To help determine whether this persistent VZV infection
of esophageal neurons is causally related to achalasia, we now propose to conduct a clinical trial of
valacyclovir to determine whether eradication of VZV alleviates achalasia symptoms and improves esophageal
function. We also plan to quantify viral load in relation to achalasia phenotypes and employ next generation
sequencing to look for a genetic basis of esophageal VZV reactivation. Finally, because mast cell accumulation
and degranulation have been reported in the achalasia esophagus and verified in our preliminary data we will
test the hypothesis that mast cell activation contributes to manifestations and/or painful symptoms of VZV-
associated achalasia. To gain insight into mechanisms of achalasia pathogenesis, we will also determine
whether VZV reactivates specifically in neurons thought to control relaxation of the lower esophageal sphincter
(nitric oxide synthase) and/or the excitatory phase of esophageal peristalsis (choline acetyltransferase). Viral
destruction of nitrergic inhibitory neurons could be a cause of failure of LES smooth muscle to relax and either
or both of these neurons could contribute to the loss of peristalsis that accompanies achalasia.

## Key facts

- **NIH application ID:** 10873309
- **Project number:** 5R01DK093094-11
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** MICHAEL D GERSHON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $575,787
- **Award type:** 5
- **Project period:** 2011-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873309

## Citation

> US National Institutes of Health, RePORTER application 10873309, VZV in the enteric nervous system: pathogenesis and consequences (5R01DK093094-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10873309. Licensed CC0.

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