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.

项目概要 蜱传立克次体病（TBRD）在世界各地普遍存在，病死率高达 尽管有有效的治疗方法，但疾病集群的范围可能高达 100%。 通过用有前景的新方法补充现有策略，增加 TBRD 控制的“工具箱” 我们最近的研究表明，重点是中断蜱虫媒介中的立克次体传播周期。 非致病性安地立克次体在进食期间在蜱唾液中分泌，但分泌量较低 与致病性帕克氏立克次体相比，其水平较高，引发了有关潜在机制的疑问 介导立克次体致病性的可能性。 水平传播已被认识，但立克次体和蜱之间的特定相互作用仍然存在 不幸的是，关于蜱传的基本传播生物学存在重大知识空白。 立克次体以及立克次体和蜱生理学之间实现传播的特定相互作用， 代表了该领域的重大障碍，并限制了新控制方法的发展 因此，该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，以增强唾液腺生理机能并增加 腺体的分泌活动，促进唾液腺功能的增加。 依赖于腺泡膜生理学的严格调节，因此，我们认为立克次体改变 离子稳态机制以促进水平传输。 抑制离子流将抵消立克次体介导的唾液腺活性增强作用，从而预防蜱虫 在具体目标 1 中，我们将采用血粉喂养和立克次体水平传播。 多学科方法测量致病性立克次体对分泌活性和 与非感染蜱相比，感染帕克里蜱唾液腺的膜生理学（例如膜电位） 这些数据将描述立克次体影响的机制。 在特定目标 2 中，我们将测试 K+ 是否失调。 唾液腺上皮细胞的稳态会抑制立克次氏蜱的唾液腺功能，从而改变血液 结合饲养生物学和降低脊椎动物疾病模型中的 R. parkeri 毒力。 他的提案中概述的将定义立克次体对蜱生理学影响的独特方面，从而增强 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问题并揭示 减少 TBRD 健康负担的干预措施。