A novel ternary virulence system in plague

鼠疫新型三元毒力系统

• 批准号: 7897846
• 负责人: SUSAN C STRALEY
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897846
• 关键词: Acute; Adherence; Aspartic Endopeptidases; Bacterial Adhesins; Cells; Complex; Culture Media; Epithelioid Cells; Evolution; Face; Family; Goals; Human; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Link; Membrane Proteins; Mus; Operon; Pasteurella pseudotuberculosis; Pathogenesis; Peptide Hydrolases; Phenotype; Plague; Plasmids; Pneumonic Plague; Role; Surface; System; Variant; Virulence; Yersinia pestis; improved; macrophage; novel; protein function; public health relevance

DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of plague in humans. We have discovered a chromosomally located bicistronic operon that encodes a novel pair of interacting surface proteins called YadB and YadC (collectively referred to as YadB-C) that belong to the trimeric autotransporter family. YadB-C promotes invasion of epithelioid cells and J774A.1 macrophage-like cells; but unlike most trimeric autotransporters appears not to promote adherence. Interestingly, invasive activity requires the presence of the surface aspartyl protease Pla, which also is an adhesin/invasin, independent of its protease activity. In addition, Pla selectively degrades YadB, causing YadB-C complexes to disappear, and its presence is required for release of a fragment of YadC into the culture medium. Like Pla, YadB-C is crucial for virulence in bubonic plague; however, it is not essential for virulence in pneumonic plague. This raises the possibility that the dominant virulence function of these proteins is directed against acute inflammation, which occurs rapidly in bubonic plague but only late in pneumonic plague. The small plasmid that encodes Pla is unique to Y. pestis, and its acquisition is believed to have been a key step in the evolution of Y. pestis from Y. pseudotuberculosis. Thus yadBC may be another link to the high virulence of Y. pestis. We hypothesize that YadB, YadC, and Pla constitute a novel ternary virulence mechanism to counteract inflammatory defenses that are mobilized early in bubonic plague. The goal of this proposed R21 project is to define the essential roles of the 3 components of this system. In Aim 1 we will exploit a set of Y. pestis strains carrying variants of these components to determine the roles of Pla, YadC, and YadB in YadB-C function in vitro. In Aim 2, we will characterize infections of normal mice and mice lacking key inflammatory cells to develop a hypothesis for the innate defense target of YadB-C. PUBLIC HEALTH RELEVANCE: These studies will contribute to our broad understanding of pathogenesis in the face of an acute inflammatory response. Accordingly, the study of YadB-C will inform studies in many other bacterial systems in addition to improving our understanding of the pathogenesis of plague.

描述（由申请人提供）：耶尔森氏菌是人类瘟疫的病因。我们发现了一个位于染色体的双散发性操纵子，该染色体编码了一对新型的相互作用的表面蛋白，称为YADB和YADC（集体称为YADB-C），该蛋白属于Trimeric Autotporter家族。 YADB-C促进上皮细胞和J774A.1巨噬细胞样细胞的侵袭。但是，与大多数三聚体自动转运蛋白不同，似乎并不促进依从性。有趣的是，侵入性活性需要表面天冬氨酸蛋白酶PLA，这也是一种粘附蛋白/invasin，与其蛋白酶活性无关。此外，PLA有选择地降解YADB，导致YADB-C复合物消失，并且其存在是将YADC片段释放到培养基中所必需的。像PLA一样，YADB-C对于泡沫鼠疫中的毒力至关重要。但是，这对于肺炎鼠疫中的毒力并不是必不可少的。这增加了这些蛋白质的主要毒力功能针对急性炎症的可能性，急性炎症迅速发生在泡沫鼠疫中，但仅在肺炎鼠疫中后期发生。编码PLA的小质粒是pestis独有的，据信其获取是Y. pseudotubercolcolisosion Y. Pestis进化的关键步骤。因此，YADBC可能是Y. Pestis高毒力的另一个联系。我们假设YADB，YADC和PLA构成了一种新型的三元毒力机制，可以抵消在Bubonic Plague早期动员的炎症防御剂。该提出的R21项目的目的是定义该系统3个组件的重要作用。在AIM 1中，我们将利用这些组件的变体的一组Y. pestis菌株，以确定PLA，YADC和YADB在YADB-C功能在体外功能中的作用。在AIM 2中，我们将表征缺乏关键炎症细胞的正常小鼠和小鼠的感染，以开发YADB-C先天防御靶标的假设。公共卫生相关性：面对急性炎症反应，这些研究将有助于我们对发病机理的广泛理解。因此，对YADB-C的研究将为我们在许多其他细菌系统的研究提供信息，除了提高我们对瘟疫发病机理的理解。