Type-I Interferons drive cell-autonomous immunity to malaria

项目摘要 由原生动物疟原虫引起的疟疾是一种毁灭性的疾病，导致近50万人死亡 每年.由蚊子传播的疟原虫在蚊子体内进行无症状的发育和复制。 肝脏，然后转化为感染红细胞并导致致命的临床疾病。因此，我们认为， 阻碍肝脏中的疟原虫感染已经被追求作为延迟、降低肝脏中的疟原虫感染的严重性或 预防临床疟疾。虽然已知自然免疫反应可以控制疟原虫感染， 肝脏，我们对这一过程的机制知之甚少。这使我们无法 利用肝脏中的先天免疫途径来开发免疫或治疗方法， 阻止或消除肝脏阶段疟原虫感染。我们小组的长期目标是了解 控制肝脏中疟原虫的先天免疫机制。本申请的目的是阻止- 1型干扰素（IFN）如何促进疟原虫从宿主肝细胞中消除。我们 中心假设是肝细胞中的1型IFN信号传导能够破坏帕拉- 谷空泡膜（PVM），以及其中包含的疟原虫通过“非典型的Au- tophagy '。我们建议确定1型干扰素招募自噬蛋白LC 3的机制。 通过溶酶体促进疟原虫的破坏 特异性目标1的降解，以及1型IFN如何使一类干扰素诱导的GTP酶，称为 鸟苷酸结合蛋白引起PVM本身的机械酶降解，以启动PVM降解途径。 特异性目标2中感染肝细胞的程序性细胞死亡。已知1型IFN诱导多个 各种细胞类型中的基因和途径。拟议研究的基本原理是，通过确定 1型干扰素信号通路的特异性分子介体，其能够消除疟原虫， 肝细胞，我们将确定新的，具体的治疗机会，以更好地控制或消除 肝脏里的疟原虫这些知识将适用于开发新的免疫预防剂， 为旅行者提供抗疟药物，或在疟疾流行地区进行大规模药物管理。这些疗法还可以 可能清除肝脏中休眠的疟原虫感染，或帮助改善减毒活抗疟疾疫苗， 针对疟疾肝脏阶段的电影候选人。我们提出的研究将采用一系列创新的 例如表达Cre重组酶的疟原虫的工具，其能够仅在宿主细胞中切除特定的宿主基因， 感染的肝细胞，以及区分疟原虫裂解与其PVM裂解的报告肝细胞。 除了使我们更接近于在根本上控制和可能消灭疟疾之外， 完成这一建议将有助于扩大我们的知识有关的改善 人类健康，推进NIH的核心使命。

PROJECT SUMMARY Malaria, caused by the protozoan Plasmodium is a devastating disease that kills close to half a million people each year. Plasmodium transmitted by mosquitoes undergo asymptomatic development and replication in the liver, before transitioning into infecting the red blood cells and causing the deadly clinical disease. Therefore, hindering Plasmodium infection in the liver has been pursued as a strategy to delay, reduce the severity of, or prevent clinical malaria. Although natural immune responses are known to control Plasmodium infection in the liver, we understand very little about the mechanisms that underlie this process. This has prevented us from harnessing the innate immune pathways in the liver to develop immunological or therapeutic approaches to impede or eliminate Plasmodium infection in its liver-stage. Our group's long-term goal is to understand the innate immune mechanisms that control Plasmodium in the liver. The objective of this application is to deter- mine how type-1 interferons (IFNs) facilitate the elimination of Plasmodium from its host hepatocytes. Our central hypothesis is that type-1 IFN signaling in the hepatocytes would enable the destruction of the para- sitophorous vacuolar membrane (PVM), as well as the Plasmodium contained in it through `non-canonical au- tophagy'. We propose to determine the mechanisms by which type-1 IFNs recruit the autophagy protein LC3 to facilitate the destruction of Plasmodium contained within the parasitophorous vacuole through lysosomal degradation in Specific Aim 1, and how type-1 IFNs enable a class of interferon induced GTPases, called guanylate binding proteins to cause mechano-enzymatic degradation of the PVM itself, to initiate a pathway of programmed cell-death in the infected hepatocytes in Specific Aim 2. Type-1 IFNs are known to induce multiple genes and pathways in various cell types. The rationale for the proposed research is that, by determining the specific molecular mediators of type-1 IFN signaling pathway that enable the elimination of Plasmodium in hepatocytes, we will have identified new, and specific therapeutic opportunities to better control or eliminate Plasmodium in the liver. This knowledge will be applicable for the development of new immunoprophylactic antimalarial drugs for travelers, or mass drug administration in malaria endemic areas. Such therapies can also potentially clear dormant Plasmodium infections in the liver, or help improve live-attenuated anti-malarial vac- cine candidates targeting the liver-stage of malaria. Our proposed research will employ a series of innovative tools such as Cre-recombinase expressing Plasmodium capable of ablating specific host genes in only the infected hepatocytes, and reporter hepatocytes that distinguish the lysis of Plasmodium from that of its PVM. In addition to taking us a step closer to the control and possible eradication of malaria, at a fundamental level, the completion of this proposal will foster the expansion of our knowledge pertinent to the improvement of human health, advancing the core mission of the NIH.