title: The role of serine protease HtrA in acute ulcerative enterocolitis and extra-intestinal immune responses during Campylobacter jejuni infection of gnotobiotic IL-10 deficient mice.
abstract: Campylobacter jejuni infections have a high prevalence worldwide and represent a significant socioeconomic burden. C. jejuni can cross the intestinal epithelial barrier as visualized in biopsies derived from human patients and animal models, however, the underlying molecular mechanisms and associated immunopathology are still not well understood. We have recently shown that the secreted serine protease HtrA (high temperature requirement A) plays a key role in C. jejuni cellular invasion and transmigration across polarized epithelial cells in vitro. In the present in vivo study we investigated the role of HtrA during C. jejuni infection of mice. We used the gnotobiotic IL-10(-/-) mouse model to study campylobacteriosis following peroral infection with the C. jejuni wild-type (WT) strain NCTC11168 and the isogenic, non-polar NCTC11168ΔhtrA deletion mutant. Six days post infection (p.i.) with either strain mice harbored comparable intestinal C. jejuni loads, whereas ulcerative enterocolitis was less pronounced in mice infected with the ΔhtrA mutant strain. Moreover, ΔhtrA mutant infected mice displayed lower apoptotic cell numbers in the large intestinal mucosa, less colonic accumulation of neutrophils, macrophages and monocytes, lower large intestinal nitric oxide, IFN-γ, and IL-6 as well as lower TNF-α and IL-6 serum concentrations as compared to WT strain infected mice at day 6 p.i. Notably, immunopathological responses were not restricted to the intestinal tract given that liver and kidneys exhibited mild histopathological changes 6 days p.i. with either C. jejuni strain. We also found that hepatic and renal nitric oxide levels or renal TNF-α concentrations were lower in the ΔhtrA mutant as compared to WT strain infected mice. In conclusion, we show here that the C. jejuni HtrA protein plays a pivotal role in inducing host cell apoptosis and immunopathology during murine campylobacteriosis in the gut in vivo.
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin Berlin, Germany.
authors: Markus M
authors: MM
authors: Heimesaat
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin Berlin, Germany.
authors: Marie
authors: M
authors: Alutis
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin Berlin, Germany.
authors: Ursula
authors: U
authors: Grundmann
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin Berlin, Germany.
authors: André
authors: A
authors: Fischer
authors: Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen/Nuremberg Erlangen, Germany.
authors: Nicole
authors: N
authors: Tegtmeyer
authors: Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen/Nuremberg Erlangen, Germany.
authors: Manja
authors: M
authors: Böhm
authors: Department of Medicine I for Gastroenterology, Infectious Disease and Rheumatology/Research Center ImmunoSciences, Charité - University Medicine Berlin Berlin, Germany.
authors: Anja A
authors: AA
authors: Kühl
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin Berlin, Germany.
authors: Ulf B
authors: UB
authors: Göbel
authors: Division of Microbiology, Department of Biology, Friedrich Alexander University Erlangen/Nuremberg Erlangen, Germany.
authors: Steffen
authors: S
authors: Backert
authors: Department of Microbiology and Hygiene, Charité - University Medicine Berlin Berlin, Germany.
authors: Stefan
authors: S
authors: Bereswill
mesh_terms: D000818:Animals; D017209:Apoptosis; D058491:Bacterial Load; D002169:Campylobacter Infections / Q000276:immunology / Q000473:pathology*; D016123:Campylobacter jejuni / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D003106:Colon / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000276:immunology / Q000473:pathology*; D017353:Gene Deletion; D005856:Germ-Free Life; D054884:Host-Pathogen Interactions; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology*; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism*
chemical_list: C556062:IL10 protein, mouse; D016753:Interleukin-10; D057057:Serine Proteases
keywords: bacterial translocation; colonization resistance; extra-intestinal immune responses; host-pathogen-interaction; innate immunity; intestinal immunopathology; systemic immune responses; ulcerative enterocolitis