Actin-based Motility and Tick Acquisition of Anaplasmataceae

描述（由申请人提供）：蜱的立克次体生物传播之前是媒介感染，首先是病原体从蜱中肠腔的血液转移到中肠上皮。宿主细胞肌动蛋白的操纵似乎是这种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它对这些生物体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性，促进与蜱虫中肠上皮的接触，从而使无形体科立克次体家族的传播周期永续化。这个应用程序的目的是了解负责什么可能是蜱宿主的立克次体感染的最初步骤的机制：具体来说，蜱血粉的运动性。该研究的中心假设是，在病原体入侵蜱虫中肠上皮细胞之前，无原体附属物相关蛋白负责肌动蛋白为基础的运动。我们计划通过追求以下具体目标来验证这一假设：(1)定义哺乳动物无浆附属物的细胞质成分；(2)描述附属物成分在蜱虫感染中的作用。提出这项研究的基本原理是，一旦了解了血液中以肌动蛋白为基础的非原形体运动，它将为这些病原体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的高度保守性以及该特性在无原体科和立克次体科中的保守性，很可能这种媒介感染机制也将在立克次体目中保守。预计这将对人类健康产生重大的积极影响，因为它将导致探索新的方法，例如在媒介感染事件中干扰立克次体对细胞骨架蛋白的操纵，以控制此类病原体的传播，这是立克次体传播周期可以被打破的关键点。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蜱虫，并将使开发新的策略来干扰这些蜱传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.