title: CsgA is a pathogen-associated molecular pattern of Salmonella enterica serotype Typhimurium that is recognized by Toll-like receptor 2.
abstract: Knowledge about the origin and identity of the microbial products recognized by the innate immune system is important for understanding the pathogenesis of inflammatory diseases. We investigated the potential role of Salmonella enterica serotype Typhimurium fimbriae as pathogen-associated molecular patterns (PAMPs) that may stimulate innate pathways of inflammation. We screened a panel of 11 mutants, each carrying a deletion of a different fimbrial operon, for their enteropathogenicity using the calf model of human gastroenteritis. One mutant (csgBA) was attenuated in its ability to elicit fluid accumulation and GROalpha mRNA expression in bovine ligated ileal loops. The mechanism by which thin curled fimbriae encoded by the csg genes contribute to inflammation was further investigated using tissue culture. The S. Typhimurium csgBA mutant induced significantly less IL-8 production than the wild type in human macrophage-like cells. Purified thin curled fimbriae induced IL-8 expression in human embryonic kidney (HEK293) cells transfected with Toll-like receptor (TLR) 2/CD14 but not in cells transfected with TLR5, TLR4/MD2/CD14 or TLR11. Fusion proteins between the major fimbrial subunit of thin curled fimbriae (CsgA) and glutathione-S-transferase (GST) elicited IL-8 production in HEK293 cells transfected with TLR2/CD14. Proteinase K treatment abrogated IL-8 production elicited in these cells by GST-CsgA, but not by synthetic lipoprotein. GST-CsgA elicited more IL-6 production than GST in bone marrow-derived macrophages from TLR2+/+ mice, while there was no difference in IL-6 secretion between GST-CsgA and GST in macrophages from TLR2-/- mice. These data suggested that CsgA is a PAMP that is recognized by TLR2.
authors.affiliation: Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616-8645, USA.
authors.forename: Cagla
authors.initials: C
authors.lastname: Tükel
authors.forename: Manuela
authors.initials: M
authors.lastname: Raffatellu
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Humphries
authors.forename: R Paul
authors.initials: RP
authors.lastname: Wilson
authors.forename: Helene L
authors.initials: HL
authors.lastname: Andrews-Polymenis
authors.forename: Tamara
authors.initials: T
authors.lastname: Gull
authors.forename: Josely F
authors.initials: JF
authors.lastname: Figueiredo
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Wong
authors.forename: Kathrin S
authors.initials: KS
authors.lastname: Michelsen
authors.forename: Mustafa
authors.initials: M
authors.lastname: Akçelik
authors.forename: L Garry
authors.initials: LG
authors.lastname: Adams
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Bäumler
mesh_terms: D018829:Adhesins, Bacterial / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D002460:Cell Line; D054360:Chemokine CXCL1; D018925:Chemokines / Q000235:genetics; D002630:Chemotactic Factors / Q000235:genetics; D004195:Disease Models, Animal; D010861:Fimbriae, Bacterial / Q000235:genetics / Q000378:metabolism*; D005759:Gastroenteritis / Q000382:microbiology; D017353:Gene Deletion; D005798:Genes, Bacterial; D006801:Humans; D007082:Ileum / Q000382:microbiology / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D015850:Interleukin-6 / Q000032:analysis; D016209:Interleukin-8 / Q000032:analysis; D009876:Operon; D012333:RNA, Messenger / Q000032:analysis; D019779:Salmonella enterica / Q000276:immunology / Q000378:metabolism* / Q000472:pathogenicity; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
chemical_list: D018829:Adhesins, Bacterial; C475896:CXCL1 protein, Bos taurus; D054360:Chemokine CXCL1; D018925:Chemokines; D002630:Chemotactic Factors; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2