Rickettsial Influence on Host Membrane Physiology in Arthropod Vectors

立克次体对节肢动物载体宿主膜生理学的影响

• 批准号: 10676614
• 负责人: Daniel Swale
• 金额: $ 51.98万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-25 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10676614
• 关键词: Acinus organ component; Address; Amblyomma; Arthropod Vectors; Arthropods; Automobile Driving; Biological Assay; Biology; Blood; Case Fatality Rates; Cells; Cessation of life; Data; Development; Disease Clusterings; Disease model; Ecology; Epidemiology; Epithelial; Gland; Health; Homeostasis; Horizontal Disease Transmission; Human; Incidence; Infection; Interruption; Intervention; Ions; Kinetics; Knowledge; Life Cycle Stages; Maintenance; Measures; Mediating; Membrane; Membrane Potentials; Methods; Modification; Molecular Genetics; Organism; Pathogenicity; Pathway interactions; Pharmacology; Physiological; Physiology; Population; Potassium; Prevalence; Protein Secretion; Proteins; Publishing; Regulation; Research; Rickettsia; Rickettsia Infections; Rickettsia parkeri; Saliva; Salivary Glands; Testing; Tick Control; Tick-Borne Diseases; Ticks; United States; Vertical Disease Transmission; Virulence; base; comparative; disorder control; effective therapy; endosymbiont; experimental study; feeding; human pathogen; innovation; interdisciplinary approach; novel; novel strategies; pathogen; pathogenic bacteria; prevent; response; saliva secretion; spotted fever; therapeutic development; tick feeding; tick saliva; tick transmission; tick-borne; tick-borne pathogen; tool; transmission process; vector; vector tick

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.

项目摘要 蜱传立克次体病（TBRD）在世界各地普遍存在， 尽管有有效的治疗方法，但疾病集群的范围可高达100%。因此，有必要 通过用有前途的新方法补充现有策略，增加TBRD控制的“工具箱” 专注于阻断蜱虫媒介中立克次体的传播周期。我们最近的研究表明 非致病性立克次体和蜱在进食期间分泌在蜱唾液中，但在较低的浓度下， 水平相比，致病性立克次体parkeri，提出了关于潜在机制的问题 介导立克次氏体致病性。立克次体操纵节肢动物宿主， 水平传播已被确认，但立克次体和蜱之间的特定相互作用仍然存在 未知不幸的是，关于蜱传病毒的基本传播生物学， 立克次体以及立克次体与蜱生理学之间的特定相互作用，使传播成为可能， 代表了该领域的一个重大障碍，并限制了新的控制方法的发展， TBRD。因此，这一建议的前提是，致病性立克次体，而不是非致病性菌株， 立克次体，改变蜱源蛋白的调节，以增强唾液腺生理学， 腺体的分泌活动，这有助于增加水平传输。唾液腺功能是 依赖于腺泡膜生理学的严格调节，因此，我们假设立克次体改变了 离子稳态的机制，以促进水平传输。相应地，我们假设， 抑制离子流将抵消立克次体介导的唾液腺活性增强，以防止蜱 血粉喂养和水平传播立克次体。在具体目标1中，我们将采用 多学科方法来测量致病性立克次体对分泌活性的影响， 膜生理学（例如膜电位）的R. parkeri感染蜱唾液腺与非感染蜱唾液腺的比较 病原性立克次体感染蜱。这些数据将阐明立克次体影响 蜱的唾液腺生理驱动致病性。在具体目标2中，我们将测试K+的失调是否 唾液腺上皮内稳态将抑制立克次体蜱唾液腺改变血液的功能 摄食生物学和降低R.脊椎动物疾病模型中的帕克氏毒力。综合起来， 在他的建议中概述的将定义立克次体对蜱生理学影响的独特方面， 立克次体的致病性，这将有助于解决SFG立克次体的流行病学和揭示 干预点，以减少TBRD的健康负担。