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: 10522139
• 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/10522139
• 关键词: Antimalarials; Apoptosis; Area; Artemisinins; Attenuated; Autophagocytosis; Behavior; Betantrone; Binding Proteins; Biochemical; Blood; Cells; Clinical; Culicidae; Cytolysis; Cytosol; Development; Disease; 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; Lead; Lipids; Liver; Lysosomes; Malaria; Malaria Vaccines; Mediating; Mediator of activation protein; 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 Oxygen Species; Relapse; Reporter; Research; Series; Severities; Signal Pathway; Signal Transduction; Societies; Therapeutic; United States National Institutes of Health; Vaccines; Vacuole; adaptive immune response; base; 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; 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.

项目摘要 原生动物疟原虫引起的疟疾是一种毁灭性疾病，可杀死近50万人 每年。蚊子传播的疟原虫经历了无症状的发育和复制 肝脏，然后过渡到感染红细胞并引起致命的临床疾病。所以， 已追求阻碍肝脏感染的疟原虫感染，以延迟，减少或 防止临床疟疾。尽管已知自然免疫反应可以控制疟原虫感染 肝脏，我们对这一过程的基础的机制一无所知。这阻止了我们 利用肝脏中的先天免疫途径，开发出免疫或治疗方法 阻碍或消除其肝阶段的疟原虫感染。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。该应用的目的是确定 挖掘1型干扰素（IFN）如何促进从其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IFN信号传导将使para- SITOPHOLOL液泡膜（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IFN募集自噬蛋白LC3的机制 促进寄生虫液体中包含的疟原虫的破坏 特定目标1中的降解以及1型IFN如何启用一类干扰素诱导的GTPase，称为 鸟苷酸结合蛋白会导致PVM本身的机械酶降解，以启动一条途径 特定目标2中感染的肝细胞中的程序性细胞死亡。已知1型IFN诱导多个 各种细胞类型的基因和途径。拟议研究的理由是，通过确定 1型IFN信号传导途径的特定分子介质，可以消除疟原虫在 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 肝脏中的疟原虫。这些知识将适用于开发新的免疫预防性 旅行者的抗疟药，或疟疾流行地区的大规模药物管理。这种疗法也可以 肝脏中潜在明显的休眠质量感染，或有助于改善活体衰减的抗疟疾真空 针对疟疾肝脏的候选者。我们提出的研究将采用一系列创新性 诸如表达疟原虫的CRE聚合酶之类的工具，仅在 感染的肝细胞和记者的肝细胞，将疟原虫与其PVM的裂解区分开。 除了使我们更接近控制和可能消除疟疾的基本水平之外， 该提案的完成将促进我们的知识的扩展，与改善有关 人类健康，推进NIH的核心使命。