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）：鼠疫耶尔森氏菌是人类鼠疫的病原体。我们发现了一个位于染色体上的双顺反子操纵子，它编码一对新型相互作用的表面蛋白，称为 YadB 和 YadC（统称为 YadB-C），属于三聚体自转运蛋白家族。 YadB-C促进上皮样细胞和J774A.1巨噬细胞样细胞的侵袭；但与大多数三聚体自动转运蛋白不同，它似乎不促进依从性。有趣的是，侵袭活性需要表面天冬氨酰蛋白酶 Pla 的存在，它也是一种粘附素/侵袭素，与其蛋白酶活性无关。此外，Pla 选择性降解 YadB，导致 YadB-C 复合物消失，并且它的存在是将 YadC 片段释放到培养基中所必需的。与 Pla 一样，YdB-C 对于黑死病的毒力至关重要。然而，这对于肺鼠疫的毒力来说并不是必需的。这提出了一种可能性，即这些蛋白质的主要毒力功能针对急性炎症，这种炎症在黑死病中迅速发生，但仅在肺鼠疫晚期发生。编码 Pla 的小质粒是鼠疫耶尔森氏菌所独有的，其获得被认为是鼠疫耶尔森氏菌从假结核耶尔森氏菌进化而来的关键步骤。因此，yadBC 可能是鼠疫耶尔森氏菌高毒力的另一个联系。我们假设 YadB、YadC 和 Pla 构成了一种新颖的三元毒力机制，可以抵消黑死病早期动员的炎症防御。这个拟议的 R21 项目的目标是定义该系统 3 个组件的基本角色。在目标 1 中，我们将利用一组携带这些组件变体的鼠疫耶尔森菌株来确定 Pla、YadC 和 YadB 在体外 YadB-C 功能中的作用。在目标 2 中，我们将描述正常小鼠和缺乏关键炎症细胞的小鼠的感染特征，以提出 YadB-C 先天防御靶点的假设。公共卫生相关性：这些研究将有助于我们对急性炎症反应的发病机制有更广泛的了解。因此，对 YadB-C 的研究除了提高我们对鼠疫发病机制的理解之外，还将为许多其他细菌系统的研究提供信息。