Novel murine infection models provide deep insights into the "ménage à trois" of Campylobacter jejuni, microbiota and host innate immunity

• Published in: PloS one Vol. 6; no. 6; p. e20953
• Main Authors: Bereswill, Stefan, Fischer, André, Plickert, Rita, Haag, Lea-Maxie, Otto, Bettina, Kühl, Anja A, Dasti, Javid I, Dashti, Javid I, Zautner, Andreas E, Muñoz, Melba, Loddenkemper, Christoph, Gross, Uwe, Göbel, Ulf B, Heimesaat, Markus M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2011; Public Library of Science (PLoS)
• Subjects: Acids; Adapter proteins; Animal models; Animals; Antibiotics; Antigens; Apoptosis; Bacteria; Biology; Campylobacter; Campylobacter coli; Campylobacter Infections - immunology; Campylobacter Infections - metabolism; Campylobacter Infections - microbiology; Campylobacter jejuni; Campylobacter jejuni - isolation & purification; Campylobacteriosis; Colon; Colonization; CpG islands; Cytokines - metabolism; Deoxyribonucleic acid; Disease Models, Animal; DNA; E coli; Escherichia coli; Fitness; Flora; Formic acid; Gastrointestinal tract; Genomes; Gnotobiotic; Guillain-Barre syndrome; Hygiene; Immune response; Immune system; Immunity; Immunity, Innate; Immunology; Infections; Inflammation; Inflammatory bowel disease; Innate immunity; Interleukin 6; Intestinal microflora; Intestine; Leukocytes (neutrophilic); Lipopolysaccharides; Lymphocytes; Lymphocytes B; Lymphocytes T; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Microbiota; Milk; Monocyte chemoattractant protein 1; Mucosa; MyD88 protein; Pathogens; Signaling; Studies; Toll-like receptors; Toxoplasma gondii; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020953

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.
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.
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.