Journal Article

West Nile virus triggers intestinal dysmotility via T cell–mediated enteric nervous system injury

Zhao, Fang R., Diamond, Michael S., Mack, Matthias, Stappenbeck, Thaddeus S., Thackray, Larissa B., Janova, Hana, Desai, Pritesh

2024

Overview

Intestinal dysmotility syndromes have been epidemiologically associated with several antecedent bacterial and viral infections. To model this phenotype, we previously infected mice with the neurotropic flavivirus West Nile virus (WNV) and demonstrated intestinal transit defects. Here, we found that within 1 week of WNV infection, enteric neurons and glia became damaged, resulting in sustained reductions of neuronal cells and their networks of connecting fibers. Using cell-depleting antibodies, adoptive transfer experiments, and mice lacking specific immune cells or immune functions, we show that infiltrating WNV-specific CD4+ and CD8+ T cells damaged the enteric nervous system (ENS) and glia, which led to intestinal dysmotility; these T cells used multiple and redundant effector molecules including perforin and Fas ligand. In comparison, WNV-triggered ENS injury and intestinal dysmotility appeared to not require infiltrating monocytes, and damage may have been limited by resident muscularis macrophages. Overall, our experiments support a model in which antigen-specific T cell subsets and their effector molecules responding to WNV infection direct immune pathology against enteric neurons and supporting glia that results in intestinal dysmotility.

• Publisher: American Society for Clinical Investigation
• Subject: Adoptive transfer / Analysis / Animal experimentation / Animals / Antigens / B cells / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD8 antigen / CD8-Positive T-Lymphocytes - immunology / Colorectal diseases / Complications and side effects / Development and progression / Effector cells / Enteric nervous system / Enteric Nervous System - immunology / Enteric Nervous System - pathology / Epidemiology / FasL protein / Gastroenterology / Gastrointestinal diseases / Gastrointestinal Motility - immunology / Gastrointestinal system / Health aspects / Infection / Infections / Infectious disease / Intestine / Intestine, Small / Lymphocytes / Lymphocytes T / Macrophages / Mice / Mice, Inbred C57BL / Monocytes / Motility / Nervous system / Nervous system, Autonomic / Neuroglia - immunology / Neuroglia - metabolism / Neuroglia - pathology / Neuronal-glial interactions / Neurons / Neurons - immunology / Neurons - metabolism / Neurons - pathology / Perforin / Perforin - genetics / Perforin - immunology / Perforin - metabolism / Phenotypes / Risk factors / Small intestine / T cells / Viral infections / Viruses / West Nile fever / West Nile Fever - immunology / West Nile Fever - pathology / West Nile virus / West Nile virus - immunology