# Systemic Neurotropic virus infection effects on GI Dysmotility

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $706,017

## Abstract

ABSTRACT
Dysfunction and/or degeneration of the enteric nervous system (ENS) can cause gastrointestinal tract
dysmotility. One particularly severe and clinically challenging dysmotility disorder in humans is chronic
intestinal pseudo-obstruction (CIPO). The most effective current therapies for CIPO are parenteral nutrition and
small bowel transplantation. New animal models to develop and test therapeutic options for CIPO are a
substantial unmet need in this area. To this end, we found that mice infected with RNA viruses of the Flavivirus
genus including West Nile (WNV) demonstrate features of CIPO that may help reveal new modes of treatment.
WNV infects enteric neurons in the submucosal and myenteric plexus of the GI tract of mice, resulting in T cell
infiltration, injury and cell death of neurons, and decreased bowel motility. The diminished bowel motility occurs
in the absence of any gross anatomic or mechanical obstructive defects. In the chronic phase, mice clear virus
infection but still have sustained GI dysmotility that resolves slowly over a few months. Remarkably, a relapse
of GI dysmotility can be triggered in the convalescent phase after WNV-infected animals are exposed to
unrelated inflammatory stimuli. To explain the relapsing/remitting nature of this disease course, we propose a
model whereby structural and function defects in the ENS in response to WNV infection and the resultant
immune response affect an enteric neuroendocrine-immune (NEI) circuit that, along with the microbiota,
becomes chronically dysregulated. In this proposal, we will test novel approaches to correct that dysregulated
NEI circuit by modulating: (i) CD8+ T cell responses that induce acute injury of enteric neurons following WNV
infection; (ii) the microbiota, which becomes dysregulated following WNV infection and can transfer the
dysmotility phenotype to uninfected mice and (iii) neuroendocrine hormones, specifically the 5-HT serotonergic
system, which appears diminished in the WNV model. Our goal is to use this mouse model to dissect the
underlying regulatory mechanisms of the NEI circuit, elucidate the interplay between the various components
of the NEI circuit and the microbiota, and understand how it malfunctions in response to viral infection. Our
group will define mechanistically how perturbation of the enteric NEI circuit following WNV infection results in
acute, chronic and relapsing GI dysmotility. This information may facilitate the development of agents that
prevent damage to or restore the function of the enteric NEI circuit and the microbiota following systemic
neurotropic virus infection, which could form the basis of therapies for CIPO and related bowel motility
disorders.

## Key facts

- **NIH application ID:** 10072267
- **Project number:** 1R01DK122790-01A1
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Michael S Diamond
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $706,017
- **Award type:** 1
- **Project period:** 2020-07-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072267

## Citation

> US National Institutes of Health, RePORTER application 10072267, Systemic Neurotropic virus infection effects on GI Dysmotility (1R01DK122790-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072267. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*