Type-I Interferons drive cell-autonomous immunity to malaria

I 型干扰素驱动细胞对疟疾的自主免疫

• 批准号: 10650860
• 负责人: Samarchith Kurup
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650860
• 关键词: Ablation; Antimalarials; Apoptosis; Area; Artemisinins; Attenuated; Autophagocytosis; Behavior; Binding Proteins; Biochemical; Blood; Cells; Clinical; Culicidae; Cytolysis; Cytosol; Development; Disease; Drug resistance; Enterobacteria phage P1 Cre recombinase; Erythrocytes; Exposure to; Fostering; Genes; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Hepatocyte; Human; Image; Immune response; Immunity; Immunologics; Immunology; In Vitro; Infection; Inflammasome; Innate Immune Response; Interferon Type I; Interferons; Knowledge; Licensing; Liver; Lysosomes; Malaria; Malaria Vaccines; Mediating; Mediator; Membrane; Mission; Molecular; Molecular Target; Morbidity - disease rate; Mus; Natural Immunity; Nature; Organism; Parasite resistance; Parasites; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasmodium; Plasmodium vivax; Population; Process; Proteins; Public Health; Publishing; Reactive Inhibition; Reactive Oxygen Species; Relapse; Reporter; Research; Series; Severities; Signal Induction; Signal Pathway; Signal Transduction; Societies; Southeastern Asia; Therapeutic; United States National Institutes of Health; Vaccines; Vacuole; adaptive immune response; burden of illness; cell type; experimental study; flexibility; global health; guanylate; improved; in vivo; innate immune mechanisms; innate immune pathways; innovation; malaria infection; mortality; novel; novel strategies; novel therapeutics; prevent; recruit; therapeutic target; tool; transmission process; vaccine candidate

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.

项目概要 疟疾由原生动物疟原虫引起，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经历无症状的发育和复制 肝脏，然后转变成感染红细胞并引起致命的临床疾病。所以， 阻碍肝脏中的疟原虫感染已被视为延缓疟原虫感染、减轻其严重程度或 预防临床疟疾。尽管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。这使得我们无法 利用肝脏中的先天免疫途径来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。此应用程序的目的是阻止 我想了解 1 型干扰素 (IFN) 如何促进从宿主肝细胞中消除疟原虫。我们的 中心假设是肝细胞中的 1 型干扰素信号传导能够破坏副细胞 sitophorous 液泡膜（PVM），以及通过“非规范au-”包含在其中的疟原虫 土噬'。我们建议确定 1 型干扰素招募自噬蛋白 LC3 的机制 促进通过溶酶体破坏寄生液泡内所含的疟原虫 具体目标 1 中的降解，以及 1 型 IFN 如何启用一类干扰素诱导的 GTP 酶，称为 鸟苷酸结合蛋白引起 PVM 本身的机械酶降解，启动一条途径 具体目标 2 中受感染肝细胞中的程序性细胞死亡。已知 1 型 IFN 可诱导多种 各种细胞类型中的基因和通路。拟议研究的基本原理是，通过确定 1 型 IFN 信号通路的特定分子介质，能够消除体内的疟原虫 肝细胞，我们将确定新的、特定的治疗机会，以更好地控制或消除 肝脏中的疟原虫。这些知识将适用于开发新的免疫预防药物 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。此类疗法还可以 可能清除肝脏中的休眠疟原虫感染，或有助于改善减毒活抗疟疾疫苗 针对疟疾肝脏阶段的候选电影。我们提出的研究将采用一系列创新 工具，例如表达疟原虫的 Cre 重组酶，能够仅消除特定宿主基因 感染的肝细胞和报告肝细胞可区分疟原虫的裂解与其 PVM 的裂解。 除了让我们在根本上更接近控制和可能根除疟疾之外， 该提案的完成将促进我们对改进相关知识的扩展 人类健康，推进 NIH 的核心使命。