H. hepaticus: the pathogenesis of IBD

描述(申请人提供)：特发性炎症性肠病(IBD)是一种病因不明的衰弱疾病。IBD的发病机制已经用靶向基因突变(基因敲除)小鼠进行了研究，这些小鼠患上了类似于人类IBD的慢性肠炎。在几个这样的基因敲除小鼠模型中，包括T细胞受体αβ(TCRαβ)、白介素2(IL-2)和白介素10(IL-10)基因敲除小鼠，已经证明无菌条件可以防止IBD的发展。似乎驻留的肠道微生物群不足以引发这些动物的疾病，但实验感染一组新出现的小鼠细菌病原体，称为肠肝螺杆菌物种，足以引起IBD。为了更好地了解这些模型中疾病的发病机制，我们建议阐明肠道-肝脏螺杆菌物种在基因敲除小鼠中引起IBD的机制。虽然获得性免疫系统在IBD的发病机制中很重要，但缺乏获得性免疫的基因敲除小鼠也容易患上幽门螺杆菌相关性IBD。为此，我们提出的研究重点是肠肝螺杆菌与天然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型螺杆菌。我们和我们的合作者最近已经确定了肝炎嗜血杆菌ATCC 51449的完整基因组序列。利用基因组序列，我们将鉴定和表征候选细菌毒力决定因素，并产生等基因突变株，在小鼠肠道上皮细胞单层和小鼠巨噬细胞培养中进行测试，并在选定的基因敲除小鼠模型中进行体内测试。这些研究将检验这样一种假设，即肠肝螺杆菌物种中离散的细菌毒力决定因素会从先天性免疫系统中引发促炎反应，在缺乏适当调节的适应性免疫系统的情况下，这会导致IBD。希望这些研究将导致开发新的治疗和预防IBD的策略。

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.