title: Internalization-dependent recognition of Mycobacterium avium ssp. paratuberculosis by intestinal epithelial cells.
abstract: Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of Johne's disease, a highly prevalent chronic intestinal infection in domestic and wildlife ruminants. The microbial pathogenesis of MAP infection has attracted additional attention due to an association with the human enteric inflammatory Crohn's disease. MAP is acquired by the faecal-oral route prompting us to study the interaction with differentiated intestinal epithelial cells. MAP was rapidly internalized and accumulated in a late endosomal compartment. In contrast to other opportunistic mycobacteria or M. bovis, MAP induced significant epithelial activation as indicated by a NF-kappaB-independent but Erk-dependent chemokine secretion. Surprisingly, MAP-induced chemokine production was completely internalization-dependent as inhibition of Rac-dependent bacterial uptake abolished epithelial activation. In accordance, innate immune recognition of MAP by differentiated intestinal epithelial cells occurred through the intracellularly localized pattern recognition receptors toll-like receptor 9 and NOD1 with signal transduction via the adaptor molecules MyD88 and RIP2. The internalization-dependent innate immune activation of intestinal epithelial cells is in contrast to the stimulation of professional phagocytes by extracellular bacterial constituents and might significantly contribute to the histopathological changes observed during enteric MAP infection.
authors.affiliation: Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Pott
authors.forename: Tina
authors.initials: T
authors.lastname: Basler
authors.forename: Claudia U
authors.initials: CU
authors.lastname: Duerr
authors.forename: Manfred
authors.initials: M
authors.lastname: Rohde
authors.forename: Ralph
authors.initials: R
authors.lastname: Goethe
authors.forename: Mathias W
authors.initials: MW
authors.lastname: Hornef
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D054426:Chemokine CXCL2 / Q000096:biosynthesis; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D004705:Endocytosis; D011992:Endosomes / Q000382:microbiology; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D054884:Host-Pathogen Interactions; D006801:Humans; D007113:Immunity, Innate; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D016927:Mycobacterium avium subsp. paratuberculosis / Q000276:immunology* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000276:immunology / Q000378:metabolism; D010283:Paratuberculosis / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse