Actin-based Motility and Tick Acquisition of Anaplasmataceae

基于肌动蛋白的无形体科运动和蜱的获取

• 批准号: 7895022
• 负责人: ROGER William STICH
• 金额: $ 18.41万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-20 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7895022
• 关键词: Actins; Anaplasma marginale; Anaplasmataceae; Animal Model; Animals; Biochemistry; Biological; Blood; Bovine Anaplasmosis; Cells; Cytoskeletal Proteins; Cytoskeleton; Development; Ehrlichiosis; Epithelial Cells; Epithelium; Erythrocytes; Evaluation; Event; F-Actin; Family; Feces; Goals; Health; Human; Immunofluorescence Immunologic; Infection; Investigation; Lead; Mammals; Methods; Microfilaments; Midgut; Modeling; Modification; Molecular; Molecular Structure; Movement; Nature; Organism; Outcome; Parasites; Pathogenesis; Pathway interactions; Proteins; Qualifying; Research; Rickettsia; Rickettsiaceae; Rickettsiales; Rocky Mountain Spotted Fever; Role; Structure; Testing; Tick-Borne Diseases; Ticks; Vacuole; Work; apical membrane; appendage; authority; base; cell motility; innovation; insight; interest; invertebrate host; novel; novel strategies; pathogen; polymerization; programs; public health relevance; trait; transmission process; vector

DESCRIPTION (provided by applicant): Biological transmission of rickettsia from ticks is preceded by infection of the vector, which starts with transfer of the pathogen from the blood meal in the tick midgut lumen to the midgut epithelium. Manipulation of host cell actin appears to be an important feature of this rickettsial infection pathway, and conservation of this trait among families of tick-borne rickettsia suggests that it is important for the survival of these organisms in nature. There is evidence that F-actin structures perpetuate the transmission cycle of the rickettsial family Anaplasmataceae by providing actin-based motility that facilitates contact with the tick midgut epithelium that is subsequently infected by the organisms. The objective of this application is to understand the mechanism responsible for what is likely to be the initial step in rickettsial infection of the tick host: specifically, motility in the tick blood meal. The central hypothesis of the proposed research is that the anaplasmal appendage associated protein is responsible for actin-based motility prior to pathogen invasion of tick midgut epithelial cells. We plan to test this hypothesis by pursuing the following specific aims: (1) to define the mammalian cytoplasmic constituents of anaplasmal appendages and (2) to delineate the role of appendage components in tick infection by A. marginale. The rationale for the proposed research is that, once anaplasmal actin-based motility in the blood meal is understood, it will provide new insights into transmission and possibly pathogenic mechanisms associated with these pathogens. Moreover, due to the highly conserved nature of the host proteins involved and the conservation of this trait among the Anaplasmataceae and the Rickettsiaceae, it is likely that this mechanism of vector infection will be also be conserved among the order Rickettsiales. This is expected to have significant positive effects on human health, because it will lead to exploration of new approaches such as interference with rickettsial manipulation of cytoskeletal proteins to control transmission of such pathogens at the vector infection event, which represents a key point where the rickettsial transmission cycle can be broken. PUBLIC HEALTH RELEVANCE There are critical gaps in our understanding of the molecular events that enable bacterial parasites of the order Rickettsiales to infect host cells. This project will establish how rickettsial pathogens exploit the host cell cytoskeletons to infect ticks and will enable development of new strategies to interfere with acquisition and subsequent transmission of these tick-borne pathogens.

描述（由申请方提供）：蜱类立克次体的生物传播之前是载体感染，首先是病原体从蜱类中肠腔的血粉转移到中肠上皮。宿主细胞肌动蛋白的操纵似乎是立克次体感染途径的一个重要特征，并且在蜱传立克次体家族中保存这一特征表明这对这些生物在自然界中的生存很重要。有证据表明，F-肌动蛋白结构通过提供肌动蛋白为基础的运动，促进与蜱中肠上皮细胞，随后被感染的生物体接触，使立克次体家族无形体科的传播周期永久化。本申请的目的是了解蜱宿主立克次体感染的初始步骤的机制：特别是蜱血餐中的运动性。这项研究的中心假设是，在病原体入侵蜱中肠上皮细胞之前，无形体附件相关蛋白负责肌动蛋白运动。我们计划通过以下具体目标来检验这一假设：（1）确定哺乳动物无形体附件的细胞质成分;（2）描述附件成分在蜱感染A.边缘。拟议研究的基本原理是，一旦理解血餐中基于无形体肌动蛋白的运动，它将为与这些病原体相关的传播和可能的致病机制提供新的见解。此外，由于所涉及的宿主蛋白质的高度保守性以及该性状在无形体科和立克次体科中的保守性，很可能该载体感染机制在立克次体目中也是保守的。预计这将对人类健康产生重大的积极影响，因为这将导致探索新的方法，如干扰立克次体对细胞骨架蛋白的操纵，以控制此类病原体在媒介感染事件中的传播，这代表了立克次体传播周期可以被打破的关键点。公共卫生相关性我们对立克次体目细菌寄生虫感染宿主细胞的分子事件的理解存在重大空白。该项目将确定立克次体病原体如何利用宿主细胞骨架感染蜱虫，并将开发新的策略来干扰这些蜱传病原体的获得和随后的传播。