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.

在健康的成年人中，tick传播的立克疾病继续引起严重的疾病和死亡， 全球儿童。在过去的六年中，立克疾病的发病率显着升高 病例死亡率高达10％。如果抗生素药 提早管理。但是，强力霉素不适用于怀孕或5岁以下的患者 年龄。因此，迫切需要基于宿主力学的治疗干预措施。我们的长期 目的是研究主要的细胞内细菌立克siae的关键宿主分子，以建立 他们在哺乳动物宿主细胞中的感染生态位。这些研究将提供有关新型免疫治疗的见解 干预措施。该提案的目标是揭示R. Australis颠覆的机制 自噬可促进巨噬细胞感染。该提议中要检验的假设是R。 澳大利亚调节和利用ATG5依赖性自噬，通过抑制成熟来促进感染 巨噬细胞中的自噬体和抵消宿主免疫控制。我们将评估 自噬抑制是一种通过中断威胁生命的立克感染的治疗策略 参与澳大利亚菌诱导的ATG5依赖性自噬体的途径。这个项目将研究这个 利用两个链接的特定目的的假设。 AIM 1将确定R.澳大利亚的机制 诱导和颠覆ATG5依赖性自噬体，以使其在巨噬细胞中的感染中受益。这 将研究ULK1在调节立克诱导的自噬体中的作用。我们将研究 MAVS/IRF7/ISG54和GTPASE RAB 25参与抗菌活性和 支持巨噬细胞感染。 AIM 2将评估自噬抑制作用作为治疗的潜力 防止威胁生命的立克感染的策略。我们将采用体内鼠标体模型 感染以研究靶向ATG5（+）自噬体为免疫治疗的潜力 通过使用调节自噬体的关键分子的特定抑制剂或刺激剂进行干预。这是 认为该提案的具体目的的完成可能会为免疫提供新的见解 治疗致命的立克毒素的治疗策略。