H. hepaticus: the pathogenesis of IBD

描述（由申请人提供）：特发性炎症性肠病（IBD）是一种病因不明的衰弱性疾病。IBD的发病机制已经使用靶向基因突变（敲除）小鼠进行了研究，这些小鼠发生慢性肠道炎症，类似于人类IBD。在几种这些敲除小鼠模型中，包括T细胞受体α β（TCR α β）、白细胞介素-2（IL-2）和IL-10敲除小鼠中，已经显示无菌条件防止IBD的发展。在这些动物中，常驻肠道微生物群似乎不足以引发疾病，但实验性感染一组称为肠肝螺杆菌的新兴鼠细菌病原体足以引起IBD。为了更好地了解这些模型中疾病的发病机制，我们建议阐明肠肝螺杆菌引起基因敲除小鼠IBD的机制。虽然适应性免疫系统在IBD的发病机制中很重要，但缺乏适应性免疫的基因敲除小鼠也易患螺杆菌相关IBD。出于这个原因，我们提出的研究集中在肝肠螺杆菌物种和先天免疫系统之间的相互作用。将对肝螺杆菌进行研究，肝螺杆菌是最具特征的肠肝螺杆菌。我们和我们的合作者最近确定了H.肝球菌ATCC 51449。利用基因组序列，我们将确定和表征候选细菌毒力决定簇，并产生同基因突变株，以测试在培养与小鼠肠上皮细胞单层和小鼠巨噬细胞，并在体内与选定的敲除小鼠模型。这些研究将检验这样的假设，即肠肝螺杆菌物种中的离散细菌毒力决定簇引起先天免疫系统的促炎反应，在缺乏适当调节的适应性免疫系统的情况下，导致IBD。希望这些研究将导致治疗和预防IBD的新策略的发展。

DESCRIPTION (provided by applicant): Idiopathic inflammatory bowel disease (IBD) is a debilitating condition with no known etiology. The pathogenesis of IBD has been studied using targeted gene mutant (knockout) mice that develop chronic intestinal inflammation, which resembles human IBD. It has been shown in several of these knockout mouse models, including T cell receptor alpha beta (TCR alpha beta), interleukin-2 (IL-2), and IL-10 knockout mice, that germ-free conditions protect against the development of IBD. It does not appear that resident intestinal microbiota are sufficient to trigger disease in these animals, but experimental infection with an emerging group of murine bacterial pathogens called enterohepatic Helicobacter species is sufficient to cause IBD. To better understand the pathogenesis of disease in these models, we propose to elucidate the mechanisms by which enterohepatic Helicobacter species cause IBD in knockout mice. Although the adaptive immune system is important in the pathogenesis of IBD, knockout mice lacking adaptive immunity are also susceptible to Helicobacter-associated IBD. For this reason, our proposed studies focus on interactions between enterohepatic Helicobacter species and the innate immune system. Studies will be carried out with Helicobacter hepaticus, the most well characterized enterohepatic Helicobacter species. We and our collaborators have recently determined the complete genome sequence of H. hepaticus ATCC 51449. Taking advantage of the genome sequence, we will identify and characterize candidate bacterial virulence determinants, and generate isogenic mutant strains to test in culture with murine intestinal epithelial cell monolayers and murine macrophages, and in vivo with selected knockout mouse models. These studies will test the hypothesis that discrete bacterial virulence determinants in enterohepatic Helicobacter species elicit proinflammatory responses from the innate immune system, which in the absence of a properly regulated adaptive immune system, lead to IBD. It is hoped that these studies will lead to the development of new strategies for the treatment and the prevention of IBD.