Mechanisms by which rickettsiae subvert autophagy pathway in macrophages

壁虱传播的立克次体疾病继续在其他健康的成年人中造成严重疾病和死亡 世界各地的儿童。在过去六年中，立克次体疾病的发病率显著增加， 病死率高达10%。如果使用抗生素，立克次体疾病患者对多西环素的反应良好 很早就给药了。然而，多西环素不宜用于妊娠或5岁以下的患者。 很多年了。因此，迫切需要基于宿主机制的治疗干预。我们的长期计划 目标是研究关键的宿主分子，通过这些分子，细胞内的里氏立克次体细菌进化成 它们在哺乳动物宿主细胞中的感染生态位。这些研究将为新的免疫疗法提供见解 干预措施。这项提案的目的是揭示澳大利亚根癌菌颠覆 促进巨噬细胞感染的自噬作用。在这项提议中要检验的假设是R。 澳大利亚通过抑制ATG5的成熟来调节和利用依赖ATG5的自噬来促进感染 巨噬细胞中的自噬小体和对抗宿主免疫控制。我们将评估 自噬抑制作为一种通过阻断自噬来对抗危及生命的立克次体感染的治疗策略 澳大利亚乳杆菌诱导依赖ATG5的自噬小体的途径。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。目标1将确定澳大利亚根结线虫 诱导和颠覆依赖ATG5的自噬小体，以利于其在巨噬细胞中的感染。这个 ULK1在调节立克次体诱导的自噬小体中的作用将被研究。我们会研究 MAVS/IRF7/ISG54和GTPase Rab 25参与拮抗抗菌活性和 支持巨噬细胞的感染。目标2将评估抑制自噬作为一种治疗方法的可能性。 预防危及生命的立克次体感染的战略。我们将采用立克次体活体小鼠模型 感染研究ATG5(+)自噬小体作为免疫治疗靶点的可能性 通过使用调节自噬小体的关键分子的特定抑制物或刺激物进行干预。它是 相信这项提案的具体目标的完成可能会为免疫系统提供新的见解 治疗致命立克次体病的治疗策略。

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.