The mechanism of Shigella flexneri adherence during the early infection process

描述(由申请者提供)：K22研究学者发展奖关注候选人克里斯蒂娜·S·法赫蒂博士成为一名独立研究员的长期研究目标，并为未来的R01申请生成更多数据。法赫蒂博士在福氏志贺氏菌致病机理方面拥有丰富的研究经验，并与该领域的专家有很强的合作关系。这一建议意义重大，因为它将开始阐明福氏志贺菌的早期定植过程，以确定黏附是否是感染的重要第一步，这是对志贺氏菌发病机制的一个主要认识空白。福氏志贺氏菌是一种兼性细胞内病原体，每年感染1.6亿人，主要是发展中国家的5岁以下儿童，导致100万人死亡，从而造成巨大的全球负担。感染是由于细菌入侵结肠上皮的能力造成的。虽然福氏志贺氏菌的入侵过程和免疫逃避已被广泛研究，但对其早期感染过程的研究还不够充分。主要来说，目前尚不清楚细菌是如何识别结肠环境的，以及福氏志贺氏菌是否在入侵前利用黏附因子附着在上皮细胞上。这项工作的中心假设是福氏链球菌利用粘附素进行接触。 在入侵前与结肠上皮接触。因此，这项提议的长期目标和目的是确定福氏志贺氏菌在入侵前毒力过程中如何识别结肠并附着在结肠上皮细胞。这项建议的具体目的是：1)鉴定福氏志贺氏菌利用粘附素附着在结肠上皮细胞顶端表面；2)鉴定促进福氏志贺氏菌黏附的上皮细胞顶端表面的蛋白质。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会抑制黏附，从而减少上皮细胞的侵袭。因此，这项拟议的研究可能会导致创新的治疗方法，或者通过靶向依从性因素来改进候选疫苗。最后，这些数据不仅可以翻译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入侵前发生的定植事件来增强当前的福氏志贺氏菌感染模式。 相关性：拟议的研究与公共卫生相关，因为它解决了福氏志贺氏菌感染过程中的关键空白，福氏志贺氏菌是一种细菌病原体，每年导致全球1.6亿例痢疾。这项研究符合国家过敏和传染病研究所的任务目标，并可能导致改进候选疫苗，以防止毁灭性的感染率。

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.