Intestinal Dysmotility Syndromes following Systemic Infection by Flaviviruses

James P. White, Shanshan Xiong, Nicole P. Malvin, William Khoury-Hanold, Robert O. Heuckeroth, Thaddeus S. Stappenbeck, Michael S. Diamond

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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. Damage caused to enteric neurons during acute flavivirus infections manifests in the form of gastrointestinal motility abnormalities that are exacerbated in later life upon challenge with either unrelated infectious or non-infectious inflammatory stimuli.

Original languageEnglish
Pages (from-to)1198-1212.e12
JournalCell
Volume175
Issue number5
DOIs
StatePublished - Nov 15 2018

Keywords

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

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