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）：该K22研究学者发展奖的重点是候选人Christina S. Faherty博士的长期研究目标，以成为独立研究者，并为未来的R01应用程序生成其他数据。 Faherty博士在Shigella Flexneri发病机理方面拥有丰富的研究经验，并与该领域的专家建立了牢固的合作关系。该提案很重要，因为它将开始阐明屈曲链球菌的早期定植过程，以确定依从性是否是感染的重要第一步，这是有关志贺氏菌发病机理的知识的主要差距。 S. flexneri是一种辅助细胞病原体，每年通过感染1.6亿人，主要是五岁以下的儿童在发展中国家的儿童，从而造成重要的全球负担，导致100万人死亡。感染是由于细菌侵袭了结肠上皮。虽然已经对屈肌的入侵过程和免疫逃避弹性进行了广泛的研究，但早期感染过程尚未得到充分研究。主要是，细菌如何识别结肠环境以及S. flexneri是否利用粘附因子在入侵之前粘附在上皮细胞上。这项工作的中心假设是S. flexneri利用粘合剂进行接触 在入侵之前与结肠上皮。因此，该提案的长期目标是确定弹性链球菌如何识别结肠并在侵入前毒力期间遵守结肠上皮。该提案的具体目的是：1）识别S. flexneri使用的Th粘附素以粘附在结肠上皮的顶部表面； 2）在上皮细胞的顶部表面上鉴定促进屈链球链球菌粘附的蛋白质。从这些目标获得的数据可能会导致未来的研究，以确定针对粘附素的抗体是否抑制粘附，这可能会减少上皮细胞的侵袭。因此，拟议的研究可以通过靶向依从性因素来导致创新治疗或改善疫苗候选者。最后，数据不仅可以转化为具有同源粘附素的其他肠道病原体，而且还可以通过建立在入侵之前发生的定植事件来增强当前的弹性链球菌感染范式。 相关性：拟议的研究与公共卫生有关，因为它解决了Shigella Flexneri感染过程中的关键差距，Shigella Flexneri是一种细菌病原体，每年在全球范围内导致1.6亿例痢疾病例。该研究实现了美国国家过敏和传染病研究所的任务目标，并可能导致改善候选疫苗以防止灾难性的感染率。