title: Novel murine infection models provide deep insights into the "ménage à trois" of Campylobacter jejuni, microbiota and host innate immunity.
abstract: BACKGROUND
  Although Campylobacter jejuni-infections have a high prevalence worldwide and represent a significant socioeconomic burden, it is still not well understood how C. jejuni causes intestinal inflammation. Detailed investigation of C. jejuni-mediated intestinal immunopathology is hampered by the lack of appropriate vertebrate models. In particular, mice display colonization resistance against this pathogen.
  
  
  RESULTS
  To overcome these limitations we developed a novel C. jejuni-infection model using gnotobiotic mice in which the intestinal flora was eradicated by antibiotic treatment. These animals could then be permanently associated with a complete human (hfa) or murine (mfa) microbiota. After peroral infection C. jejuni colonized the gastrointestinal tract of gnotobiotic and hfa mice for six weeks, whereas mfa mice cleared the pathogen within two days. Strikingly, stable C. jejuni colonization was accompanied by a pro-inflammatory immune response indicated by increased numbers of T- and B-lymphocytes, regulatory T-cells, neutrophils and apoptotic cells, as well as increased concentrations of TNF-α, IL-6, and MCP-1 in the colon mucosa of hfa mice. Analysis of MyD88(-/-), TRIF(-/-), TLR4(-/-), and TLR9(-/-) mice revealed that TLR4- and TLR9-signaling was essential for immunopathology following C. jejuni-infection. Interestingly, C. jejuni-mutant strains deficient in formic acid metabolism and perception induced less intestinal immunopathology compared to the parental strain infection. In summary, the murine gut flora is essential for colonization resistance against C. jejuni and can be overcome by reconstitution of gnotobiotic mice with human flora. Detection of C. jejuni-LPS and -CpG-DNA by host TLR4 and TLR9, respectively, plays a key role in immunopathology. Finally, the host immune response is tightly coupled to bacterial formic acid metabolism and invasion fitness.
  
  
  CONCLUSIONS
  We conclude that gnotobiotic and "humanized" mice represent excellent novel C. jejuni-infection and -inflammation models and provide deep insights into the immunological and molecular interplays between C. jejuni, microbiota and innate immunity in human campylobacteriosis.
authors.affiliation: Department of Microbiology and Hygiene, Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Bereswill
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.forename: Rita
authors.initials: R
authors.lastname: Plickert
authors.forename: Lea-Maxie
authors.initials: LM
authors.lastname: Haag
authors.forename: Bettina
authors.initials: B
authors.lastname: Otto
authors.forename: Anja A
authors.initials: AA
authors.lastname: Kühl
authors.forename: Javid I
authors.initials: JI
authors.lastname: Dasti
authors.forename: Javid I
authors.initials: JI
authors.lastname: Dashti
authors.forename: Andreas E
authors.initials: AE
authors.lastname: Zautner
authors.forename: Melba
authors.initials: M
authors.lastname: Muñoz
authors.forename: Christoph
authors.initials: C
authors.lastname: Loddenkemper
authors.forename: Uwe
authors.initials: U
authors.lastname: Gross
authors.forename: Ulf B
authors.initials: UB
authors.lastname: Göbel
authors.forename: Markus M
authors.initials: MM
authors.lastname: Heimesaat
mesh_terms: D000818:Animals; D002169:Campylobacter Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D016123:Campylobacter jejuni / Q000302:isolation & purification*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D016207:Cytokines