Molecular Mechanisms of Campylobacter Jejuni-induced Pathogenesis

空肠弯曲菌诱发发病的分子机制

• 批准号: 7798712
• 负责人: Christian Jobin
• 金额: $ 19.23万
• 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/7798712
• 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菌 (C. jejuni) 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 2-300 万例病例。此外，空肠弯曲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，空肠弯曲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。尽管空肠弯曲菌感染是一个严重的健康问题，但有关宿主反应和微生物引发疾病的分子机制的信息有限。缺乏模拟空肠弯曲菌诱导的发病机制的小鼠模型可能导致了这一知识空白。在初步研究中，我们观察到与空肠弯曲菌相关的IL-10-/-； NF?BEGFP 小鼠出现严重的血性腹泻和与 NF?B 激活相关的肠道炎症。在本提案中，我们假设源自肠上皮细胞和骨髓细胞的 NFκB 信号传导有助于宿主对空肠弯曲菌感染的反应以及肠道稳态的重建。因此，NFκB 信号传导的不适当的时间和空间（细胞）激活将对宿主产生病理后果，导致无法清除微生物并发生炎症。我们将用两个具体目标来检验我们的假设：1) 剖析 NF?B 信号传导在空肠弯曲菌介导的发病机制中的细胞贡献。 2)确定RelA依赖性基因对空肠弯曲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确定肠上皮细胞和骨髓源性 NF?B 信号在宿主对空肠弯曲菌反应中的作用和功能。我们的目标是选择性删除 IL-10-/- 小鼠肠细胞和骨髓细胞中的 RelA（NF?B 亚基），以解决 NF?B 信号在宿主对空肠弯曲菌反应中的功能。该提案的最终目标是在分子水平上了解宿主对空肠弯曲菌感染的反应，并确定各种信号事件在发病机制发展中的功能参与。这种知识的获得可用于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。未来的目标包括鉴定与细菌发病机制相关的空肠弯曲菌毒力因子。 公共卫生相关性：空肠弯曲菌 (C.jejuni) 感染已成为全球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。尽管存在这种健康和社会经济负担，科学界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的疾病的新治疗替代方案的设计产生了负面影响。该项目通过基因去除易感小鼠品系 IL-10-/- 中的 NFκB 转录亚基 RelA (p65)，研究空肠弯曲菌诱导的发病机制的分子机制。该项目将阐明肠细胞和骨髓源性 NF?B 信号在宿主对空肠弯曲菌感染反应中的功能。这一新知识将极大地有助于了解空肠弯曲菌发病机制，并可能导致新治疗策略的设计。