Role of the Yersinia pestis Ail protein in plague

鼠疫耶尔森菌 Ail 蛋白在鼠疫中的作用

• 批准号: 7468431
• 负责人: Gregory V Plano
• 金额: $ 18.76万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468431
• 关键词: Anti-Bacterial Agents; Bacteria; Bacterial Adhesins; Bacterial Adhesion; Blood; Blood-Borne Pathogens; Cell Communication; Cell-Matrix Junction; Cells; Complement; Cytolysis; Data; Defect; Disease; Drug Delivery Systems; Epithelial; Epithelial Cells; Exhibits; Family member; Fleas; Genes; Genome; Goals; Heating; Hela Cells; Host Defense; Human; Immunotherapy; In Vitro; Injection of therapeutic agent; Lead; Mediating; Pathogenesis; Phagocytosis; Pharmaceutical Preparations; Plague; Play; Process; Protein Family; Proteins; Resistance; Role; Serum; Surface; System; Type III Secretion System Pathway; Vaccines; Virulence; Virulence Factors; Yersinia enterocolitica; Yersinia enterocolitica Ail protein; Yersinia pestis; genome sequencing; killings; macrophage; mutant; pathogen; prevent; small molecule; trait; vector

DESCRIPTION (provided by applicant): Yersinia pestis, the causative agent of plague is constitutively serum resistant; however, the mechanism by which this bacterium avoids destruction via complement-mediated lysis is not understood. The Y. pestis KIM and C092 genomes both encode four Ail family members. Ail family proteins play a critical role in bacteria-host cell interaction and in the resistance to complement-mediated killing in other bacterial pathogens, including Y. enterocolitica. Preliminary studies demonstrated that the Y. pestis ailC gene product is essential for survival in normal human serum, but not in heat-inactivated serum. Additional studies revealed that the AilC protein was essential for the efficient type III secretion system (T3SS)-mediated injection of Yops into epithelial (HeLa) cells, suggesting that AilC plays a critical role in host cell attachment or delivery of T3S effector proteins. This project will further characterize the role of the Y. pestis AilC protein in the pathogenesis of plague. The goals of this project are (i) to determine the role of AilC in the resistance of Y. pestis to complement-mediated killing and (ii) to determine the role of AilC in bacterial adhesion, invasion, Yop injection and bacterial virulence. Y. pestis grows, multiplies and is even transmitted in blood; therefore, this pathogen must avoid destruction via complement-mediated lysis and/or bacterial phagocytosis. Preliminary data suggests that the AilC protein is surface-exposed, highly expressed protein that plays an important role in both of these processes. The proposed studies will further characterize the role of AilC in the pathogenesis of plague and validate AilC as a potential vaccine candidate and/or a target for small molecules or immunotherapies. To produce disease in humans the bacterium Yersinia pestis must be able to survive in human blood. We have identified a Y. pestis protein called AilC that is essential to thwart blood defense systems that normally kill bacteria. Studies presented in this proposal will determine how the AilC protein protects the bacterium, a process that could be a target for new anti-bacterial drugs.

描述(由申请人提供)：鼠疫耶尔森氏菌是鼠疫的病原体，对血清具有结构性抵抗力；然而，这种细菌通过补体介导的裂解避免破坏的机制尚不清楚。鼠疫杆菌KIM和C092基因组都编码四个AIL家族成员。All家族蛋白在细菌-宿主细胞相互作用和抵抗补体介导的杀灭包括小肠结肠炎耶尔森菌在内的其他细菌病原体中发挥着关键作用。初步研究表明，鼠疫杆菌ailC基因产物在正常人血清中是生存所必需的，但在热灭活血清中不是。更多的研究表明，AilC蛋白对于高效的III型分泌系统(T3SS)介导的YOPs注射上皮细胞(HeLa)是必不可少的，这表明AilC在宿主细胞附着或运送T3S效应蛋白方面起着关键作用。该项目将进一步确定鼠疫杆菌AilC蛋白在鼠疫发病机制中的作用。本项目的目标是(I)确定AilC在鼠疫杆菌对补体介导的杀伤的抗性中的作用；(Ii)确定AilC在细菌黏附、侵袭、YOP注射和细菌毒力中的作用。鼠疫杆菌生长、繁殖，甚至在血液中传播；因此，这种病原体必须避免通过补体介导的裂解和/或细菌吞噬来破坏。初步数据表明，AilC蛋白是表面暴露的、高表达的蛋白，在这两个过程中都发挥着重要作用。拟议的研究将进一步确定AilC在鼠疫发病机制中的作用，并验证AilC作为潜在的候选疫苗和/或小分子或免疫疗法的靶点。要在人类身上制造疾病，鼠疫耶尔森氏菌必须能够在人类血液中存活。我们已经确定了一种名为AilC的鼠疫耶尔森氏菌蛋白，它对于挫败通常杀死细菌的血液防御系统至关重要。这项提案中提出的研究将确定AilC蛋白如何保护细菌，这一过程可能成为新的抗菌药物的靶点。