Mechanisms of Cytosolic Clearance of Rickettsiae

描述(由申请人提供)： 立克次体是一种细胞内细菌，可能在世界各地引发危及生命的疾病。立克次体具有侵入宿主细胞、快速逃离吞噬体空泡并在细胞质内复制的能力。自噬针对自噬小体中的细胞质成分，并在自溶酶体/溶酶体中降解它们。自噬现在被认为是细胞内监视系统的基石。拟议项目的目标是确定立克次体与自噬的相互作用及其贡献。 来控制致命的立克次体疾病。我们假设立克次体在感染早期诱导自噬，介导胞质立克次体的降解，从而对致死性立克次体疾病产生有效的宿主保护性免疫。在第一个目标中，我们将使用小鼠模型来确定自噬是否由立克次体诱导，以及自噬是否有助于宿主对致命立克次体疾病的控制。在第二个目标中，我们将确定在致命性立克次体疾病期间，自噬如何调节IL-1的反应。该项目的成功完成将突出自噬在宿主控制细胞内病原体方面的作用。拟议的项目将为细胞内微生物引起的致命传染病的预防和治疗干预提供有针对性的自噬的重要信息。

DESCRIPTION (provided by applicant): Rickettsiae are intracellular bacteria that potentially cause life-threatening diseases all over th world. Rickettsiae possess the ability to invade host cells, quickly escape phagosomal vacuoles, and replicate in the cytoplasm. Autophagy targets cytoplasmic constituents in the autophagosomes and degrades them in the autolysosomes/lysosomes. Autophagy is now considered as a cornerstone of the intracellular surveillance system. The objective of the proposed project is to determine the interaction of rickettsiae with autophagy and its contribution to host control of fatal rickettsial diseases. We hypothesize that rickettsiae induce autophagy at the early stage of infection, which mediates degradation of cytosolic rickettsiae resulting in efficient host protective immunity of fatal rickettsial diseases. In the first Aim, we will determie whether autophagy is induced by rickettsiae and whether autophagy contributes to host control of fatal rickettsial diseases using a mouse model. In the second aim, we will identify how autophagy regulates the IL-1¿ response during fatal rickettsial diseases. The successful completion of the project will highlight the role of autophagy in host control of intracellular pathogens. The proposed project will provide important information on targeting autophagy for preventive and therapeutic interventions of fatal infectious diseases caused by intracellular microbes.