Mechanisms by which rickettsiae subvert autophagy pathway in macrophages

立克次体破坏巨噬细胞自噬途径的机制

• 批准号: 10461972
• 负责人: Rong Megan Fang
• 金额: $ 20万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-04 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461972
• 关键词: 5 year old; Achievement; Address; Adult; Animal Model; Anti-Bacterial Agents; Antibiotics; Autophagocytosis; Autophagolysosome; Autophagosome; Bacteria; C3H/HeN Mouse; Case Fatality Rates; Case Study; Cell model; Cells; Cessation of life; Child; Cytosol; Development; Disease; Disease Progression; Doxycycline; Endosomes; Goals; Guanosine Triphosphate Phosphohydrolases; Human; Immune; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Infection; Infection Control; Inflammasome; Interferons; Interleukin-1 beta; Interruption; Knowledge; Life; Link; MAPK8 gene; Mediating; Mus; Nutrient; Pathogenesis; Pathway interactions; Patients; Persons; Pilot Projects; Pregnancy; Production; Proteins; Public Health; Reporting; Research; Rickettsia; Rickettsia Infections; Rickettsia conorii; Role; Testing; Therapeutic; Therapeutic Intervention; Tick-Borne Diseases; base; effective therapy; experience; in vivo; inhibition of autophagy; inhibitor; innovation; insight; macrophage; mouse model; novel; novel therapeutic intervention; pathogen; rab GTP-Binding Proteins; response; tick-borne

Tick-borne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and children worldwide. The incidence rate of rickettsial diseases significantly increased in the past six years with case fatality rate as high as 10%. Patients with rickettsial diseases respond well to doxycycline if the antibiotics are administered early. However, doxycycline is not appropriate for patients in pregnancy or under age of 5 years old. Therefore, host-mechanisms based therapeutic interventions are urgently needed. Our long term goal is to study the key host molecules by which obligately intracellular bacteria, rickettsiae, evolve to establish their infection niche in mammalian host cells. These studies will provide insights into novel immune therapeutic interventions. The objectives of this proposal are to reveal the mechanisms by which R. australis subvert autophagy to facilitate infection in macrophages. The hypothesis to be tested in this proposal is that R. australis modulates and exploits Atg5-dependent autophagy to facilitate infection via inhibiting the maturation of autophagosomes and counteracting host immune controls in macrophages. We will evaluate the potential of autophagy inhibition as a therapeutic strategy against life-threatening rickettsial infection by interrupting the pathways involved in R. australis-induced Atg5-dependent autophagosomes. This project will study this hypothesis utilizing two linked specific aims. Aim 1 will determine the mechanisms by which R. australis induces and subverts Atg5-dependent autophagosomes for the benefit of their infection in macrophages. The role of ULK1 in regulating rickettsiae-induced autophagosomes will be investigated. We will study the involvement of MAVS/IRF7/ISG54 and GTPase Rab 25 in counteracting the antibacterial activity and supporting infection in macrophages. Aim 2 will evaluate the potential of autophagy inhibition as a therapeutic strategy against life-threatening rickettsial infection. We will employ the in vivo mouse model of rickettsial infection to investigate the potential of targeting Atg5 (+) autophagosomes as immune-therapeutic interventions by using specific inhibitors or stimulators of key molecules regulating autophagosomes. It is believed that completion of the specific aims of this proposal may provide novel insights into immuno- therapeutic strategies for treating fatal rickettsioses.

蜱传立克次体疾病继续在健康成人中造成严重疾病和死亡， 世界各地的儿童。立克次体病的发病率在过去六年中显著上升， 病死率高达10%。立克次体病患者对强力霉素反应良好， 要及早管理。然而，强力霉素不适合怀孕或5岁以下的患者 岁因此，迫切需要基于宿主机制的治疗干预。我们的长期 目的是研究专性胞内细菌立克次体进化以建立 它们在哺乳动物宿主细胞中的感染小生境。这些研究将为新型免疫治疗提供见解 干预措施。本研究的目的是揭示R.南方颠覆 自噬以促进巨噬细胞中的感染。在这个建议中要检验的假设是，R。 australis调节并利用Atg 5依赖的自噬通过抑制成熟来促进感染 自噬体和抵消宿主免疫控制的巨噬细胞。我们将评估 自噬抑制作为一种治疗策略，通过中断 参与R. australis诱导的Atg 5依赖性自噬体。本项目将对此进行研究 利用两个相互关联的特定目标的假设。目的1将确定R. australis 诱导和破坏Atg 5依赖性自噬体，以利于它们在巨噬细胞中的感染。的 将研究ULK 1在调节立克次氏体诱导的自噬体中的作用。我们会研究 MAVS/IRF 7/ISG 54和GTCRab 25参与抵消抗菌活性， 支持巨噬细胞感染。目的2将评估自噬抑制作为治疗的潜力 针对威胁生命立克次体感染的策略。我们将采用立克次体的体内小鼠模型 感染，以研究靶向Atg 5（+）自噬体作为免疫治疗的潜力 通过使用调节自噬体的关键分子的特异性抑制剂或刺激剂进行干预。是 相信完成这项提案的具体目标可能会为免疫学提供新的见解， 用于治疗致命性立克次体病的治疗策略。