H. hepaticus: the pathogenesis of IBD

特发性炎症性肠病(IBD)是一种病因不明的衰弱疾病。这个 IBD的发病机制已经用靶向基因突变(敲除)小鼠进行了研究，这些小鼠发展为慢性 肠道炎症，类似于人类IBD。它已经在几个这样的基因敲除小鼠中表现出来 模型，包括T细胞受体αβ(TCRαβ)、白细胞介素2(IL-2)和IL-10基因敲除小鼠， 无菌条件可以防止IBD的发展。看起来不像是常驻肠道 微生物区系足以在这些动物中引发疾病，但实验感染一种新出现的 一组被称为肠肝螺杆菌的小鼠病原体足以引起IBD。至 为了更好地理解这些模型中的疾病发病机制，我们建议通过以下方法来阐明其机制 哪种肠道-肝脏螺杆菌导致基因敲除小鼠的IBD。虽然适应性免疫 系统在IBD的发病机制中起重要作用，缺乏获得性免疫的基因敲除小鼠也是 易患幽门螺杆菌相关性IBD。出于这个原因，我们建议的研究集中在交互作用上 肠肝螺杆菌与先天免疫系统之间的关系。研究将在以下情况下进行 肝螺杆菌，最具特征的肠肝螺杆菌物种。我们和我们的 合作者最近确定了肝片吸虫ATCC 51449的完整基因组序列。拿走 利用基因组序列的优势，我们将鉴定和表征候选细菌的毒力 并产生等基因突变株，用于与小鼠肠上皮细胞的培养试验 单层和小鼠巨噬细胞，以及体内选定的基因敲除小鼠模型。这些研究将 检验肠道-肝脏幽门螺杆菌中离散的细菌毒力决定因素引起的假设 来自先天免疫系统的促炎反应，在缺乏适当调节的情况下 适应性免疫系统，导致IBD。希望这些研究将导致新的 IBD的治疗和预防策略。

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.