Molecular Mechanisms of Campylobacter Jejuni-induced Pathogenesis

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）是世界范围内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2-3百万病例。此外，空肠梭菌感染与感染后并发症有关，如关节炎和神经退行性疾病Guillian-Barri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道外疾病。虽然空肠梭菌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。缺乏模拟空肠梭菌诱导发病机制的小鼠模型可能导致了这一知识差距。在初步研究中，我们观察到益生菌大肠杆菌相关的IL-10-/-；NF吗?BEGFP小鼠出现了严重的血性腹泻和与NF？B激活。在这个提议中，我们假设NF？来自肠上皮细胞和骨髓细胞的B信号有助于宿主对空肠梭菌感染的反应和肠道稳态的重建。因此，不适当的时间和空间（细胞）激活NF？B信号会对宿主产生病理后果，导致微生物清除失败和炎症的发生。我们将用两个特定的目的来检验我们的假设：1)解剖NF的细胞贡献？B信号在空肠梭菌介导的发病机制中的作用。2)确定rela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确定肠细胞和骨髓源性NF的作用和功能。宿主对空肠梭菌反应中的B信号。我们的目标是选择性地删除RelA (NF？B亚基)在IL-10-/-小鼠肠细胞和髓细胞中的作用，以解决NF？B信号在宿主对空肠梭菌应答中的作用。本研究的最终目标是在分子水平上了解宿主对空肠梭菌感染的反应，并确定各种信号事件在发病机制发展中的功能参与。这种知识的获得可以用来调节这种致病微生物对宿主的有害影响，并帮助设计有效的预防措施。未来的目标包括表征空肠梭菌致病的毒力因子。

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.