Yersinia Yops in an Animal Infection Model

描述（由申请人提供）：致病菌克服宿主防御，在粘膜表面和哺乳动物组织中建立感染。因此，了解发生在这些位点的细菌-宿主相互作用对于理解宿主防御和免疫至关重要。致病性耶尔森氏菌、假结核耶尔森氏菌、鼠疫耶尔森氏菌和小肠结肠炎耶尔森氏菌都含有一种毒力质粒pYV，该质粒编码III型分泌装置的成分以及效应蛋白Yops。III型分泌系统将Yops注入哺乳动物细胞，在那里它们破坏和/或改变哺乳动物细胞功能。大多数Yops在培养细胞中具有多种蛋白靶点和生化活性。然而，它们在动物感染模型中的细胞靶点尚不清楚。YopH和YopE是关键的毒力因子，允许耶尔森菌定植许多组织并引起疾病。通过研究感染动物模型系统中对特定宿主蛋白有作用缺陷的YopH和YopE突变体，YopH和YopE必须灭活才能使耶尔森菌定植组织并引起疾病的蛋白靶点将被确定。此外，还将鉴定在感染过程中注射YopH和YopE的宿主细胞，以及在不同组织中杀死YopH和YopE突变体的宿主细胞类型。综合这些知识，这些知识将揭示YopH和YopE在不同组织中针对的宿主防御，以及YopH和YopE阻挠这些宿主防御所需的特定活动，从而使耶尔森菌定植并引起疾病。该项目的长期目标是了解耶尔森氏菌在动物组织中定植和引起疾病的所有Yops的作用，并了解宿主在组织中预防、对抗和/或控制耶尔森氏菌感染的防御机制。

DESCRIPTION (provided by applicant): Pathogenic bacteria overcome host defenses to establish infections at mucosal surfaces and in mammalian tissues. Thus, understanding bacterial-host interactions that occur at these sites is critical to understanding host defenses and immunity. Pathogenic Yersinia spps, Y. pseudotuberculosis, Y. pestis and Y. enterocolitica all contain a virulence plasmid, pYV, that encodes components of a type III secretion apparatus as well as effector proteins, called Yops. The type III secretion system injects Yops into mammalian cells where they disrupt and/or alter mammalian cell function. Most Yops have multiple protein targets and biochemical activities in cultured cells. However, their cellular targets in an animal infection model are unknown. YopH and YopE are crucial virulence factors that allow Yersinia to colonize many tissues and cause disease. By studying mutants of YopH and YopE that are defective in acting on specific host proteins in an animal model system of infection, the protein targets that YopH and YopE must inactivate to enable Yersinia to colonize tissues and cause disease will be defined. In addition, the host cells that are injected with YopH and YopE during infection and the host cell types that kill yopH and yopE mutants in different tissues will be identified. Combined, this knowledge will reveal the host defenses targeted by YopH and YopE in different tissues and the specific activities of YopH and YopE needed to thwart these host defenses to enable Yersinia to colonize and cause disease. The long-term goals of this project are to understand the role of all Yops for Yersinia spp. to colonize and cause disease in animal tissues and to understand the host defenses that prevent, combat and/or contain Yersinia infection in tissues.