The mechanism of Shigella flexneri adherence during the early infection process

早期感染过程中福氏志贺氏菌的粘附机制

• 批准号: 8485328
• 负责人: Christina S Faherty
• 金额: $ 16.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8485328
• 关键词: 5 year old; Address; Adherence; Affect; Age; Antibiotic Resistance; Antibodies; Antigen-Presenting Cells; Apical; Award; Bacillary Dysentery; Bacteria; Bacterial Adhesins; Bile fluid; Binding; Biological Assay; Candidate Disease Gene; Cells; Cessation of life; Child; Colon; Data; Developing Countries; Development; Disease; Doctor of Philosophy; Dysentery; Ensure; Environment; Epithelial Cells; Epithelium; Event; Future; Genes; Goals; Growth; Immune; Infection; Invaded; Knowledge; Lead; M cell; Membrane; Microbial Biofilms; Mission; National Institute of Allergy and Infectious Disease; Pathogenesis; Pattern; Process; Proteins; Public Health; RNA Sequences; Research; Research Personnel; Reverse Transcription; Scanning Electron Microscopy; Shigella; Shigella flexneri; Signal Transduction; Structure; Surface; Technology; Testing; Translating; Vaccines; Virulence; Work; bile salts; design; enteric pathogen; experience; improved; in vivo; innovation; meetings; mutant; pathogen; prevent; receptor; vaccine candidate

DESCRIPTION (provided by applicant): This K22 Research Scholar Development Award focuses on the long-term research goals of the candidate, Christina S. Faherty, Ph.D., to become an independent investigator and to generate additional data for a future R01 application. Dr. Faherty has extensive research experience in Shigella flexneri pathogenesis, and has a strong collaborative relationship with experts in the field. The proposal is significant because it will begin to elucidate the early colonization process of S. flexneri to determine if adherence is an important first step in infection, which is a major gap in knowledge regarding Shigella pathogenesis. S. flexneri is a facultative-intracellular pathogen that causes a significan global burden by infecting 160 million people annually, predominately in children under the age of five years in developing countries, resulting in 1 million deaths. Infection is due to the abiliy of the bacteria to invade the colonic epithelium. While the invasion process and immune evasion of S. flexneri have been extensively studied, the early infection process has not been adequately investigated. Principally, it remains unknown how the bacteria recognize the colonic environment and if S. flexneri utilizes adherence factors to adhere to epithelial cells prior to invasion. The central hypothesis of this work is that S. flexneri utilizes adhesins to make contact with the colonic epithelium prior to invasion. Therefore, the long-term goals and objectives of this proposal are to determine how S. flexneri recognizes the colon and adheres to the colonic epithelium during pre-invasion virulence. The specific aims of this proposal are to: 1) identify th adhesins utilized by S. flexneri to adhere to the apical surface of the colonic epithelium; and 2) identify proteins on the apical surface of epithelial cells that facilitate S. flexneri adherence. he data obtained from these aims could lead to future studies to determine if antibodies directed against the adhesins inhibit adherence, which could reduce invasion of epithelial cells. Therefore, the proposed research could lead to innovative treatments or an improved vaccine candidate by targeting adherence factors. Finally, the data could not only translate to other enteric pathogens with homologous adhesins, but could also enhance the current S. flexneri infection paradigm by establishing the colonization events that occur prior to invasion. RELEVANCE: The proposed research is relevant to public health because it addresses key gaps in the infection process of Shigella flexneri, a bacterial pathogen that causes 160 million cases of dysentery each year around the globe. The research meets the goals of the mission for the National Institutes of Allergy and Infectious Diseases, and may lead to improved vaccine candidates to prevent the devastating infection rates.

描述（由申请人提供）：这个K22研究学者发展奖侧重于候选人的长期研究目标，克里斯蒂娜S。Faherty博士，成为一名独立的调查员，并为将来的R 01申请生成额外的数据。Faherty博士在福氏志贺菌发病机制方面具有丰富的研究经验，并与该领域的专家有着很强的合作关系。这一建议具有重要意义，因为它将开始阐明S. flexneri来确定粘附是否是感染的重要第一步，这是关于志贺氏菌发病机制的知识的主要空白。S.弗氏菌是一种兼性细胞内病原体，每年感染1.6亿人，主要是发展中国家5岁以下儿童，造成100万人死亡，从而造成重大的全球负担。感染是由于细菌侵入结肠上皮的能力。同时对S.虽然已经对福氏杆菌进行了广泛的研究，但早期感染过程尚未得到充分的研究。主要是，细菌如何识别结肠环境以及S. Flexneri利用粘附因子在侵入前粘附于上皮细胞。这项工作的中心假设是S。Flexneri利用粘附素进行接触 与结肠上皮细胞接触因此，本建议的长期目标和目的是确定S。弗氏菌识别结肠并在侵袭前毒性期间粘附于结肠上皮。本研究的具体目的是：1）鉴定S. flexneri粘附到结肠上皮的顶端表面;和2）鉴定上皮细胞顶端表面上促进S. flexneri依从性。从这些目标中获得的数据可能导致未来的研究，以确定针对粘附素的抗体是否抑制粘附，这可能减少上皮细胞的侵袭。因此，拟议的研究可能会通过针对依从性因素来带来创新治疗方法或改进的候选疫苗。最后，这些数据不仅可以转化为具有同源粘附素的其他肠道病原体，而且还可以增强目前的S。通过建立在入侵之前发生的定殖事件来确定福氏杆菌感染范例。 相关性：这项拟议中的研究与公共卫生有关，因为它解决了福氏志贺菌感染过程中的关键空白，福氏志贺菌是一种细菌病原体，每年在地球仪各地导致1.6亿例痢疾。这项研究符合国家过敏和传染病研究所的使命的目标，并可能导致改进的候选疫苗，以防止毁灭性的感染率。