Role of the Yersinia pestis Ail protein in plague

描述（由申请人提供）：鼠疫耶尔森氏菌，鼠疫病原体具有本构性血清抗性；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。鼠疫杆菌的KIM和C092基因组都编码4个Ail家族成员。所有家族蛋白在细菌-宿主细胞相互作用和对其他细菌病原体（包括小肠结肠炎耶氏菌）补体介导杀伤的抗性中发挥关键作用。初步研究表明，鼠疫杆菌ailC基因产物在正常人血清中存活是必需的，但在热灭活血清中不存在。进一步的研究表明，AilC蛋白对于III型分泌系统（T3SS）介导的Yops注射到上皮细胞（HeLa）中至关重要，这表明AilC在宿主细胞附着或传递T3S效应蛋白中起着关键作用。本项目将进一步确定鼠疫耶尔森菌AilC蛋白在鼠疫发病机制中的作用。该项目的目标是：(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在细菌粘附、入侵、Yop注射和细菌毒力中的作用。鼠疫杆菌生长、繁殖，甚至通过血液传播；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蛋白是一种表面暴露的高表达蛋白，在这两个过程中都起着重要作用。拟议的研究将进一步表征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。要在人类中产生疾病，鼠疫杆菌必须能够在人类血液中存活。我们已经确定了一种叫做AilC的鼠疫杆菌蛋白，它对阻止通常杀死细菌的血液防御系统至关重要。本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标。

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.