Molecular Mechanisms of Campylobacter Jejuni-induced Pathogenesis

空肠弯曲菌诱发发病的分子机制

• 批准号: 8135463
• 负责人: Christian Jobin
• 金额: $ 22.47万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8135463
• 关键词: Acute; Address; Arthritis; Bacteria; Breeding; Campylobacter jejuni; Chronic; Communities; Development; Diarrhea; Disease; Enterocytes; Epithelial Cells; Event; Excision; Failure; Future; Genes; Genetic; Gnotobiotic; Goals; Health; Homeostasis; Immune response; In Vitro; Infection; Inflammation; Inflammatory disease of the intestine; Interleukin-10; Intestinal Diseases; Intestines; Intracellular translocation; Knowledge; Lead; Measures; Mediating; Medical; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; NF-kappa B; Neurodegenerative Disorders; Pathogenesis; Preventive; Role; Signal Transduction; Syndrome; Testing; United States; Virulence Factors; design; foodborne; gastrointestinal; in vivo; microorganism; novel therapeutics; p65; public health relevance; recombinase; villin

DESCRIPTION (provided by applicant): The Gram-negative invasive bacterium Campylobacter jejuni (C. jejuni) is the leading cause of bacterial food-borne gastrointestinal illness worldwide, with approximately 2-3 million annual cases in the United States alone. In addition, C. jejuni infection is associated with post-infectious complications such as arthritis and the neurodegenerative disorder Guillian-Barri syndrome. Therefore, C. jejuni infection has the potential to cause both acute/chronic intestinal disorders and debilitating extra-intestinal illnesses. Although C. jejuni infection represents a serious health concern, limited information is available on both host responses and the molecular mechanisms by which the microorganism triggers diseases. The lack of a murine model mimicking C. jejuni induced pathogenesis likely contributed to this gap of knowledge. In preliminary studies, we observed that gnotobiotic C. jejuni-associated IL-10-/-; NF?BEGFP mice developed severe bloody diarrhea and intestinal inflammation associated with NF?B activation. In this proposal, we hypothesize that NF?B signaling derived from intestinal epithelial cells and myeloid cells contributes to the host response to C. jejuni infection and to the reestablishment of intestinal homeostasis. Consequently, improper temporal and spatial (cellular) activation of NF?B signaling will have pathological consequences for the host, leading to failure to clear the microorganism and development of inflammation. We will test our hypothesis with two SPECIFIC AIMS: 1) Dissect the cellular contribution of NF?B signaling in C. jejuni mediated pathogenesis. 2) Determine the impact of RelA-dependent genes on C. jejuni translocation and intracellular survival. This project will utilize both in vivo and in vitro approaches to define the role and function of enterocyte and myeloid-derived NF?B signaling in the host response to C.jejuni. Our goal is to selectively delete RelA (NF?B subunit) in enterocytes and myeloid cells of IL-10-/- mice to address the function of NF?B signaling in the host response to C. jejuni. The ultimate goal of this proposal is to understand, at the molecular level, host responses to C. jejuni infection and to determine the functional involvement of various signaling events in the development of the pathogenesis. This gain of knowledge could be utilized to modulate the deleterious impact of this pathogenic microorganism on the host and help design effective preventive measures. Future goals include the characterization of C. jejuni virulence factors responsible for the pathogenesis of the bacterium. PUBLIC HEALTH RELEVANCE: Campylobacter jejuni (C.jejuni) infection has become the predominant cause of bacterial-food borne diarrheal diseases worldwide with up to 2.4 million cases annually in the United States alone. Despite this health and socio-economical burden, the scientific and medical community knows little about the host response to this pathogenic microorganism. This gap of knowledge negatively impact on the design of new therapeutic alternative to control for C.jejuni mediated illnesses. This project investigates the molecular mechanism of C. jejuni-induced pathogenesis through genetic removal of the NF?B transcriptional subunit RelA (p65) in the susceptible murine strain IL-10-/-. The project will elucidate the function of enterocyte- and myeloid-derived NF?B signaling in host responses to C. jejuni infection. This new knowledge would significantly contribute to the understanding of C. jejuni pathogenesis and could lead to the design of new therapeutic strategies.

描述（由申请人提供）：革兰氏阴性侵入性细菌空肠弯曲杆菌（C.空肠弯曲菌）是全世界细菌性食源性胃肠道疾病的主要原因，仅在美国每年就有大约2-3百万例病例。此外，C.空肠感染与感染后并发症如关节炎和神经变性疾病格林-巴利综合征有关。因此，C.空肠感染有可能引起急性/慢性肠道疾病和使人衰弱的肠外疾病。虽然C.空肠感染是一个严重的健康问题，但关于宿主反应和微生物引发疾病的分子机制的信息有限。缺乏模拟C.空肠诱导的发病机制可能导致了这一知识空白。在初步研究中，我们观察到知生C。空肠相关IL-10-/-; NF？BEGFP小鼠严重的血性腹泻和肠道炎症与NF？B激活。在这项建议中，我们假设，NF？来源于肠上皮细胞和骨髓细胞的B信号有助于宿主对C的应答。空肠感染和肠道内稳态的重建。因此，不适当的时间和空间（细胞）激活NF？B信号传导将对宿主产生病理后果，导致无法清除微生物和炎症的发展。我们将测试我们的假设有两个具体的目标：1）解剖NF的细胞贡献？C中的B信号。空肠介导的发病机制。2)确定RelA依赖基因对C.空肠移位和细胞内存活。该项目将利用在体内和体外的方法来定义的作用和功能的肠上皮细胞和髓源性NF？B信号在宿主对C. jejuni的反应中。我们的目标是选择性地删除RelA（NF？B亚单位）在肠细胞和髓样细胞的IL-10-/-小鼠，以解决NF？主机中的B信令响应C。空肠。这项建议的最终目标是在分子水平上了解宿主对C.空肠感染，并确定在发病机制的发展中的各种信号事件的功能参与。这些知识的获得可以用来调节这种病原微生物对宿主的有害影响，并帮助设计有效的预防措施。未来的目标包括C.空肠毒力因子负责细菌的发病机制。 公共卫生相关性：空肠弯曲杆菌（C.jejuni）感染已成为全世界细菌性食源性腹泻病的主要原因，仅在美国每年就有高达240万例病例。尽管有这种健康和社会经济负担，科学和医学界对宿主对这种病原微生物的反应知之甚少。这种知识差距对控制空肠弯曲菌介导疾病的新治疗替代方案的设计产生了负面影响。本项目主要研究了C. jejuni-induced发病机制，通过遗传去除的NF？B转录亚基RelA（p65）在易感鼠品系IL-10-/-中的表达。该项目将阐明肠细胞和骨髓源性NF？宿主对C的应答中的B信号。空肠感染这些新的知识将大大有助于理解C。空肠的发病机制，并可能导致新的治疗策略的设计。