Type-I Interferons drive cell-autonomous immunity to malaria

项目总结 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体内无症状发育和复制 在转变为感染红细胞并导致致命的临床疾病之前，肝脏会受到感染。因此， 阻止肝脏中的疟原虫感染一直是一种策略，以延迟、降低或 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，我们对这一过程背后的机制知之甚少。这阻止了我们 利用肝脏中的先天免疫途径开发免疫学或治疗方法 阻止或消除肝脏阶段的疟原虫感染。我们团队的长期目标是了解 控制肝脏中疟原虫的先天免疫机制。这项申请的目的是阻吓- 我的第一型干扰素(IFN)如何促进从宿主肝细胞中消除疟原虫。我们的 中心假说是，肝细胞中的1型干扰素信号将使副... 谷胱甘肽液泡膜(PVM)以及其中所含的疟原虫通过“非典型性的Au”。 吞噬‘。我们建议确定1型干扰素募集自噬蛋白LC3的机制 以促进通过溶酶体破坏包含在寄生虫液泡内的疟原虫 特定目标1的降解，以及1型IFN如何激活一类干扰素诱导的GTP酶，称为 鸟苷结合蛋白导致PVM本身的机械酶降解，从而启动一条途径 感染肝细胞中特定目的的程序性细胞死亡2.已知的1型干扰素可诱导多发性 不同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在体内清除疟原虫的作用 肝细胞，我们将确定新的和特定的治疗机会，以更好地控制或消除 肝脏中的疟原虫。这一认识将适用于新的免疫预防药物的开发 旅行者的抗疟疾药物，或疟疾流行地区的大规模药物管理。这种疗法还可以 潜在地清除肝脏中潜伏的疟原虫感染，或有助于改善减毒活的抗疟疾疫苗- 针对肝期疟疾的候选电影。我们提议的研究将采用一系列创新的 表达疟原虫的Cre重组酶等工具仅能在 感染的肝细胞，以及区分疟原虫和其PVM的裂解的报告肝细胞。 除了使我们离控制和可能根除疟疾更近一步外，在根本上， 这项建议的完成将促进我们扩大与改善 人类健康，推进美国国立卫生研究院的核心使命。

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.