Host recognition by pathogenic yersiniae

描述(申请人提供)：鼠疫耶尔森氏菌是鼠疫的病原体，是一种高致病性生物，传播迅速，导致极高的人类死亡率。尽管它对有限的抗生素小组敏感，但它非凡的致病性， 具有生物工程抗生素耐药性的雾化细菌的潜在武器化，以及缺乏有效的疫苗或治疗方法是主要问题，这有助于将其归类为一级生物制剂。外膜蛋白Ail是鼠疫杆菌的毒力因子，由于其两个主要活性：(I)介导鼠疫杆菌与宿主细胞的黏附，以及(Ii)提供对人类补体的抵抗力，因此是治疗开发的首选候选蛋白。这个项目的重点是了解它的黏附活性，作为开发它作为新的治疗靶点的一步。工作假说是，AIL与一种或多种宿主蛋白结合，触发宿主细胞内信号级联反应，并将细菌因子转移到宿主细胞内，阻止吞噬作用，使细菌能够在细胞外存活。黏附是这一系列事件的第一个关键步骤；然而，AIL如何调节细菌对人类细胞的黏附？分子信息匮乏。该项目的具体目标旨在通过获得有关AIL的黏附活动以及与其人类宿主伙伴的相互作用的功能和结构信息来填补这一明显的空白。

DESCRIPTION (provided by applicant): Yersinia pestis, the causative agent of plague, is a highly pathogenic organism that spreads rapidly and causes extremely high human mortality. Although it is sensitive to a restricted panel of antibiotics, its extraordinary pathogenicity, the potential weaponization of aerosolized bacteria with bio-engineered antibiotic resistance, and the lack of an effective vaccine or therapy are major concerns, contributing to its classification as a Tier 1 Biothreat Agent. The outer membrane protein Ail is a Y. pestis virulence factor and a prime candidate for therapeutic development due to its two principal activities: (i) mediating the adhesion of Y. pestis bacteria to host cells, and (ii) providing resistance to human complement. This project focuses on understanding its adhesion activity as a step towards its development as a novel therapeutic target. The working hypothesis is that Ail binds one or more host proteins, triggering host intracellular signaling cascades and the translocation of bacterial factors into the host cell that block phagocytosis and enable bacteria to survive extracellularly. Adhesion is the first key step in this series of events; however, how does Ail mediate bacterial adhesion to human cells? Molecular information is lacking. The specific aims of this project are designed to fill this glaring gap by obtaining functional and structural information about the adhesion activity of Ail and the interactions with its human host partners.