Department of Microbiology and Hygiene, Charité - University Medicine Berlin, Berlin, Germany.
Department of Medical Microbiology, University Medical Center Göttingen, Göttingen, Germany.
PLoS One. 2014 Feb 25;9(2):e90148. doi: 10.1371/journal.pone.0090148. eCollection 2014.
Although Campylobacter jejuni infections have a high prevalence worldwide and represent a significant socioeconomic burden, the underlying molecular mechanisms of induced intestinal immunopathology are still not well understood. We have recently generated a C. jejuni mutant strain NCTC11168::cj0268c, which has been shown to be involved in cellular adhesion and invasion. The immunopathological impact of this gene, however, has not been investigated in vivo so far.
METHODOLOGY/PRINCIPAL FINDINGS: Gnotobiotic IL-10 deficient mice were generated by quintuple antibiotic treatment and perorally infected with C. jejuni mutant strain NCTC11168::cj0268c, its complemented version (NCTC11168::cj0268c-comp-cj0268c), or the parental strain NCTC11168. Kinetic analyses of fecal pathogen loads until day 6 post infection (p.i.) revealed that knockout of cj0268c did not compromise intestinal C. jejuni colonization capacities. Whereas animals irrespective of the analysed C. jejuni strain developed similar clinical symptoms of campylobacteriosis (i.e. enteritis), mice infected with the NCTC11168::cj0268c mutant strain displayed significant longer small as well as large intestinal lengths indicative for less distinct C. jejuni induced pathology when compared to infected control groups at day 6 p.i. This was further supported by significantly lower apoptotic and T cell numbers in the colonic mucosa and lamina propria, which were paralleled by lower intestinal IFN-γ and IL-6 concentrations at day 6 following knockout mutant NCTC11168::cj0268c as compared to parental strain infection. Remarkably, less intestinal immunopathology was accompanied by lower IFN-γ secretion in ex vivo biopsies taken from mesenteric lymphnodes of NCTC11168::cj0268c infected mice versus controls.
CONCLUSION/SIGNIFICANCE: We here for the first time show that the cj0268c gene is involved in mediating C. jejuni induced immunopathogenesis in vivo. Future studies will provide further deep insights into the immunological and molecular interplays between C. jejuni and innate immunity in human campylobacteriosis.
尽管空肠弯曲菌感染在全球范围内患病率很高，并且给社会经济带来了重大负担，但诱导肠道免疫病理学的潜在分子机制仍未得到很好的理解。我们最近生成了一株空肠弯曲菌突变株 NCTC11168::cj0268c，该突变株被证明与细胞黏附和入侵有关。然而，到目前为止，该基因在体内的免疫病理影响尚未被研究。
方法/主要发现：通过五重抗生素处理生成无菌 IL-10 缺陷型小鼠，并经口感染空肠弯曲菌突变株 NCTC11168::cj0268c、其互补株（NCTC11168::cj0268c-comp-cj0268c）或亲本株 NCTC11168。感染后第 6 天的粪便病原体载量动力学分析表明，敲除 cj0268c 并不影响肠道空肠弯曲菌的定植能力。无论分析的空肠弯曲菌菌株如何，动物都会出现类似的弯曲菌病（即肠炎）临床症状，但与感染对照组相比，感染 NCTC11168::cj0268c 突变株的小鼠的小肠和大肠长度明显更长，表明空肠弯曲菌诱导的病理学不那么明显。在感染后第 6 天，结肠黏膜和固有层中的凋亡和 T 细胞数量显著降低，与亲本株感染相比，空肠弯曲菌 NCTC11168::cj0268c 敲除突变株感染后 6 天的肠道 IFN-γ 和 IL-6 浓度也降低，这一结果得到了进一步的支持。值得注意的是，与对照组相比，来自 NCTC11168::cj0268c 感染小鼠肠系膜淋巴结的离体活检中 IFN-γ 的分泌减少伴随着较低的肠道免疫病理学。
结论/意义：我们首次表明 cj0268c 基因参与了体内空肠弯曲菌诱导的免疫发病机制。未来的研究将进一步深入了解人类弯曲菌病中弯曲菌与固有免疫之间的免疫学和分子相互作用。
