title: Clostridium difficile flagella predominantly activate TLR5-linked NF-κB pathway in epithelial cells.
abstract: Clostridium difficile has become the most common enteropathogen responsible for intestinal nosocomial post-antibiotic infections. This has coincided with the appearance of serious cases related to the emergence of hypervirulent strains. The toxins are the main virulence factors and elicit an inflammatory response during C. difficile infection. However, other bacterial components appear to be involved in the inflammatory process. In some pathogens, flagella play a role in pathogenesis through abnormal stimulation of the TLR5-mediated host immune response. To date, few studies have addressed this role for C. difficile flagella. In the current study, we confirm in two different epithelial cell models that C. difficile thanks to its FliC flagellin interacts with TLR5. In addition, thanks to inhibition and transcriptomic studies we demonstrate that the interaction of flagellin and TLR5 predominantly activates the NF-κB and, in a lesser degree, the MAPK pathways, via TLR5, leading to up-regulation of pro-inflammatory gene expression and synthesis of pro-inflammatory mediators. These results suggest a role for C. difficile flagella in contributing to inflammatory response in host intestinal cells.
authors.affiliation: Faculté de Pharmacie, "Unité Bactéries Pathogènes et Santé" (UBaPS), Univ. Paris-Sud, Université Paris-Saclay, 5, Rue Jean-Baptiste Clément, 92296, Châtenay-Malabry Cedex, France.
authors.forename: Jameel
authors.initials: J
authors.lastname: Batah
authors.affiliation: Faculté de Pharmacie, "Unité Bactéries Pathogènes et Santé" (UBaPS), Univ. Paris-Sud, Université Paris-Saclay, 5, Rue Jean-Baptiste Clément, 92296, Châtenay-Malabry Cedex, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Denève-Larrazet
authors.affiliation: Faculté de Pharmacie, "Unité Bactéries Pathogènes et Santé" (UBaPS), Univ. Paris-Sud, Université Paris-Saclay, 5, Rue Jean-Baptiste Clément, 92296, Châtenay-Malabry Cedex, France.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Jolivot
authors.affiliation: Clostridia Research Group, Centre for Biomolecular Sciences, School of Life Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kuehne
authors.affiliation: Faculté de Pharmacie, "Unité Bactéries Pathogènes et Santé" (UBaPS), Univ. Paris-Sud, Université Paris-Saclay, 5, Rue Jean-Baptiste Clément, 92296, Châtenay-Malabry Cedex, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Collignon
authors.affiliation: Faculté de Pharmacie, "Unité Bactéries Pathogènes et Santé" (UBaPS), Univ. Paris-Sud, Université Paris-Saclay, 5, Rue Jean-Baptiste Clément, 92296, Châtenay-Malabry Cedex, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marvaud
authors.affiliation: Faculté de Pharmacie, "Unité Bactéries Pathogènes et Santé" (UBaPS), Univ. Paris-Sud, Université Paris-Saclay, 5, Rue Jean-Baptiste Clément, 92296, Châtenay-Malabry Cedex, France. Electronic address: imad.kansau@u-psud.fr.
authors.forename: Imad
authors.initials: I
authors.lastname: Kansau
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D016360:Clostridioides difficile / Q000502:physiology*; D003015:Clostridium Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism* / Q000382:microbiology*; D005407:Flagella / Q000378:metabolism*; D005408:Flagellin / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D051198:Toll-Like Receptor 5; D005408:Flagellin
keywords: Clostridium difficile; Flagella; Flagellin; Innate immune response; MAPK; NF-κB; Pro-inflammatory cytokines; TLR5 signaling