Rickettsial Influence on Host Membrane Physiology in Arthropod Vectors

项目总结 壁虱传播的立克次体疾病(TBRD)在世界各地普遍存在，在 尽管提供了有效的治疗，但疾病聚集性的范围可达100%。因此，有必要 通过用有前景的新方法补充现有战略来增加TBRD控制的“工具箱” 专注于阻断立克次体在森林媒介中的传播周期。我们最近的研究表明 非致病的安氏念珠菌在取食过程中从硬蜱的唾液中分泌，但分泌量较低。 与致病性帕氏立克次体比较时的水平，提出了关于潜在机制的问题 介导立克次体致病性的物质。立克次体操纵节肢动物宿主以增强 水平传播已被认识到，但立克次体和壁虱之间的特定相互作用仍然存在 未知。不幸的是，关于壁虱传播的基本生物学存在着重大的知识空白。 立克次体和立克次体之间的特定相互作用，使传播成为可能，这 是该领域的一个重大障碍，并限制了新的控制方法的发展 TBRDS。因此，这一建议的前提是致病性立克次体，而不是非致病性立克次体 立克次体，改变壁虱衍生蛋白的调节，以增强唾液腺生理和增加 腺体的分泌活动，这有助于增加水平传递。唾液腺功能是 依赖于腺泡膜生理的严格调节，因此，我们假设立克次体改变 促进水平传播的离子稳态机制。相应地，我们假设 抑制离子通量将抵消立克次体介导的增强唾液腺活性以预防扁虱的作用 血粉喂养和立克次体水平传播。在具体目标1中，我们将采用 多学科方法测量致病性立克次体对分泌活动和 感染帕氏杆菌的硬蜱唾液腺的膜生理学(如膜电位)比较 感染了致病性立克次体的硬蜱。这些数据将描绘立克次体影响的机制 扁虱唾液腺的生理学驱使致病性。在特定的目标2中，我们将测试K+的失调 跨越涎腺上皮的动态平衡将抑制立克次体的唾液腺功能以改变血液 在脊椎动物疾病模型中摄食生物学和降低帕克氏杆菌毒力。综合起来，这些实验 他的提案中概述的将定义立克次体对扁虱生理影响的独特方面，这些方面增强了 立克次体的致病性，将有助于解决SFG立克次体的流行病学和揭示 干预措施旨在减轻TBRDS的健康负担。

PROJECT SUMMARY Tick-borne rickettsial diseases (TBRDs) are ubiquitously present throughout the world and case fatality rates in disease clusters can range up to 100% despite the availability of effective treatment. Thus, there is a need to increase the “tool box” for TBRD control by supplementing existing strategies with promising novel approaches that focus on interrupting the Rickettsia transmission cycle in the tick vector. Our recent studies demonstrated that the non-pathogenic Candidatus Rickettsia andeanae is secreted in tick saliva during feeding, but at a lower level when compared to pathogenic Rickettsia parkeri, raising questions regarding the underlying mechanisms that mediate rickettsial pathogenicity. The likelihood that rickettsiae manipulate the arthropod host to enhance horizontal transmission has been recognized, yet the specific interactions between Rickettsia and ticks remains unknown. Unfortunately, significant knowledge gaps exist regarding the basic transmission biology of tick-borne Rickettsia and the specific interactions between Rickettsia and tick physiology that enable transmission, which represents a significant barrier to the field and has limited the development of novel approaches to control TBRDs. Thus, the premise of this proposal is that pathogenic Rickettsia, but not non-pathogenic strains of Rickettsia, alter regulation of tick-derived proteins to enhance salivary gland physiology and increase the secretory activity of the gland, which facilitates increased horizontal transmission. Salivary gland function is dependent on strict regulation of acini membrane physiology and thus, we hypothesize that Rickettsia alter mechanisms for ionic homeostasis to facilitate horizontal transmission. Correspondingly, we hypothesize that inhibition of ion flux will negate the rickettsial-mediated enhancement of salivary gland activity to prevent tick bloodmeal feeding and horizontal transmission of Rickettsia. In Specific Aim 1, we will employ a multidisciplinary approach to measure the influence pathogenic Rickettsia has to secretory activity and membrane physiology (e.g. membrane potential) of an R. parkeri infected tick salivary gland compared to non- pathogenic Rickettsia infected ticks. These data will delineate the mechanism by which Rickettsia influences tick salivary gland physiology to drive pathogenicity. In Specific Aim 2, we will test if dysregulation of K+ homeostasis across salivary gland epithelia will inhibit salivary gland function of rickettsemic ticks to alter blood feeding biology and reduce R. parkeri virulence in vertebrate disease models. Combined, the experiments outlined in his proposal will define unique aspects of rickettsial influence on tick physiology that enhance pathogenicity of Rickettsia, which will assist in resolving the epidemiology of SFG Rickettsia and reveal intervention points to reduce the health burden of TBRDs.