Actin-based Motility and Tick Acquisition of Anaplasmataceae

描述(由申请人提供)：立克次体生物传播之前，媒介的感染，首先病原体从壁虱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这一立克次体感染途径的一个重要特征，而这一特征在硬壳病传播的立克次体家族中的保守表明，它对这些生物在自然界中的生存是重要的。有证据表明，F-肌动蛋白结构通过提供基于肌动蛋白的运动性，促进与随后被该生物感染的硬蜱中肠上皮的接触，从而延长了立克次体无浆体科的传播周期。这项应用的目的是了解可能是硬体立克次体感染宿主的最初步骤的机制：具体地说，是硬体血粉中的运动性。这项研究的中心假设是，在病原体入侵硬蜱中肠上皮细胞之前，非浆附属物相关蛋白负责基于肌动蛋白的运动。我们计划通过追求以下特定目标来验证这一假说：(1)确定哺乳动物无浆体附肢的细胞质成分；(2)描述附属物成分在边际硬蜱感染中的作用。这项拟议研究的基本原理是，一旦了解了血粉中基于无浆肌动蛋白的运动，它将为传播和可能与这些病原体相关的致病机制提供新的见解。此外，由于寄主蛋白的高度保守性，以及这一特性在无浆体科和立克次体中的保守性，这种媒介感染机制很可能也将在立克次体中保守。预计这将对人类健康产生重大积极影响，因为它将导致探索新的方法，例如干扰立克次体对细胞骨架蛋白的操纵，以控制病原体在媒介感染事件中的传播，这是打破立克次体传播循环的关键。公共卫生相关性我们对使立克次体菌目的细菌寄生虫能够感染宿主细胞的分子事件的理解存在严重差距。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扁虱，并将能够开发新的策略来干扰这些由硬蜱传播的病原体的获取和随后的传播。

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.