title: Intestinal epithelium-specific MyD88 signaling impacts host susceptibility to infectious colitis by promoting protective goblet cell and antimicrobial responses.
abstract: Intestinal epithelial cells (IECs), including secretory goblet cells, form essential physiochemical barriers that separate luminal bacteria from underlying immune cells in the intestinal mucosa. IECs are common targets for enteric bacterial pathogens, with hosts responding to these microbes through innate toll-like receptors that predominantly signal through the MyD88 adaptor protein. In fact, MyD88 signaling confers protection against several enteric bacterial pathogens, including Salmonella enterica serovar Typhimurium and Citrobacter rodentium. Since IECs are considered innately hyporesponsive, it is unclear whether MyD88 signaling within IECs contributes to this protection. We infected mice lacking MyD88 solely in their IECs (IEC-Myd88(-/-)) with S. Typhimurium. Compared to wild-type (WT) mice, infected IEC-Myd88(-/-) mice suffered accelerated tissue damage, exaggerated barrier disruption, and impaired goblet cell responses (Muc2 and RELMβ). Immunostaining revealed S. Typhimurium penetrated the IECs of IEC-Myd88(-/-) mice, unlike in WT mice, where they were sequestered to the lumen. When isolated crypts were assayed for their antimicrobial actions, crypts from IEC-Myd88(-/-) mice were severely impaired in their antimicrobial activity against S. Typhimurium. We also examined whether MyD88 signaling in IECs impacted host defense against C. rodentium, with IEC-Myd88(-/-) mice again suffering exaggerated tissue damage, impaired goblet cell responses, and reduced antimicrobial activity against C. rodentium. These results demonstrate that MyD88 signaling within IECs plays an important protective role at early stages of infection, influencing host susceptibility to infection by controlling the ability of the pathogen to reach and survive at the intestinal mucosal surface.
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ganive
authors: G
authors: Bhinder
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Martin
authors: M
authors: Stahl
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ho Pan
authors: HP
authors: Sham
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Shauna M
authors: SM
authors: Crowley
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Vijay
authors: V
authors: Morampudi
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Udit
authors: U
authors: Dalwadi
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Caixia
authors: C
authors: Ma
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Kevan
authors: K
authors: Jacobson
authors: Division of Gastroenterology, Department of Pediatrics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada bvallance@cw.bc.ca.
authors: Bruce A
authors: BA
authors: Vallance
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000276:immunology*; D044082:Citrobacter rodentium / Q000276:immunology; D003092:Colitis / Q000276:immunology* / Q000382:microbiology; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000382:microbiology; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology; D005759:Gastroenteritis / Q000276:immunology / Q000382:microbiology; D041981:Gastrointestinal Tract / Q000276:immunology / Q000382:microbiology; D020397:Goblet Cells / Q000276:immunology* / Q000382:microbiology; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology; D012486:Salmonella typhimurium / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000890:Anti-Infective Agents; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88