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）：革兰氏阴性侵袭性细菌空肠弯曲杆菌（C. jejuni）是全球细菌性食品传播胃肠道疾病的主要原因，仅在美国，每年约有2-3万例病例。此外，空肠梭菌感染与感染后并发症有关，例如关节炎和神经退行性疾病吉利安 - 巴里综合征。因此，空肠梭菌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。尽管空肠梭菌感染代表了严重的健康问题，但有关宿主反应和微生物触发疾病的分子机制的信息有限。缺乏模仿梭状芽孢杆菌引起的发病机理的鼠模型可能导致了这一知识差距。在初步研究中，我们观察到gnotobiotic C. jejuni相关IL-10 - / - ; NF？BEGFP小鼠患有严重的血腥腹泻和与NF？B激活相关的肠炎。在该提案中，我们假设源自肠上皮细胞和髓样细胞的NF？B信号传导有助于宿主对jejuni感染的宿主反应以及重新建立肠稳态。因此，NF？b信号传导的时间和空间（细胞）激活不当会对宿主产生病理后果，从而导致无法清除微生物和炎症的发育。我们将以两个具体的目的检验我们的假设：1）在空肠梭菌介导的发病机理中剖析NF？b信号的细胞贡献。 2）确定依赖性基因对空肠梭菌易位和细胞内存活的影响。该项目将利用体内和体外方法来定义肠上皮细胞和髓样衍生的NF？b信号在宿主对C.Jejuni的响应中的作用和功能。我们的目标是在IL-10 - / - 小鼠的肠细胞和髓样细胞中有选择性地删除Rela（NF？B亚基），以在主机对Jejuni的响应中解决NF？B信号的功能。该提案的最终目标是在分子水平上了解宿主对空肠梭状芽胞杆菌感染的反应，并确定各种信号事件在发病机理发展中的功能参与。这种知识的增益可用于调节这种致病性微生物对宿主的有害影响，并有助于设计有效的预防措施。未来的目标包括负责细菌发病机理的空肠梭状芽孢杆菌毒力因子的表征。 公共卫生相关性：弯曲杆菌（C.Jejuni）感染已成为全球细菌食品腹泻疾病的主要原因，仅在美国，每年在美国每年多达240万例病例。尽管有这种健康和社会经济负担，但科学和医学界对宿主对这种致病性微生物的反应一无所知。知识的差距对新的治疗替代方案的设计产生负面影响，以控制C.Jejuni介导的疾病。该项目通过遗传去除NF？b转录亚基rela（p65）的遗传去除，研究了空肠梭菌诱导的发病机理的分子机制（p65）。该项目将阐明肠球菌和髓样衍生的NF？b信号在宿主对梭菌感染的反应中的功能。这种新知识将大大有助于理解空肠梭菌的发病机理，并可能导致新的治疗策略的设计。