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Cell. 2018 Nov 15;175(5):1198-1212.e12. doi: 10.1016/j.cell.2018.08.069. Epub 2018 Oct 4.

Intestinal Dysmotility Syndromes following Systemic Infection by Flaviviruses.

Author information

1
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
4
Department of Pediatrics, the Children's Hospital of Philadelphia Research Institute, the Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, PA 19104, USA.
5
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: stappenb@wustl.edu.
6
Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: diamond@wusm.wustl.edu.

Abstract

Although chronic gastrointestinal dysmotility syndromes are a common worldwide health problem, underlying causes for these disorders are poorly understood. We show that flavivirus infection of enteric neurons leads to acute neuronal injury and cell death, inflammation, bowel dilation, and slowing of intestinal transit in mice. Flavivirus-primed CD8+ T cells promote these phenotypes, as their absence diminished enteric neuron injury and intestinal transit delays, and their adoptive transfer reestablished dysmotility after flavivirus infection. Remarkably, mice surviving acute flavivirus infection developed chronic gastrointestinal dysmotility that was exacerbated by immunization with an unrelated alphavirus vaccine or exposure to a non-infectious inflammatory stimulus. This model of chronic post-infectious gastrointestinal dysmotility in mice suggests that viral infections with tropism for enteric neurons and the ensuing immune response might contribute to the development of bowel motility disorders in humans. These results suggest an opportunity for unique approaches to diagnosis and therapy of gastrointestinal dysmotility syndromes.

KEYWORDS:

enteric nervous system; gastrointestinal motility; immunopathology; pathogenesis; virus infection

PMID:
30293866
PMCID:
PMC6309989
[Available on 2019-11-15]
DOI:
10.1016/j.cell.2018.08.069

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