Enabling Host Processes for Defense Against Liver Stage Malaria Infection

启用主机进程防御肝期疟疾感染

• 批准号: 9348873
• 负责人: Emily R Derbyshire
• 金额: $ 231.18万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348873
• 关键词: Cell membrane; Cells; Chemicals; Country; Development; Disease; Drug Targeting; Drug resistance; Emergency Situation; Event; Gene Expression; Gene Proteins; Genes; Genetic Screening; Growth; Hepatocyte; Human; Infection; Infectious Agent; Liver; Malaria; Membrane; Modeling; Morphology; Nutrient; Parasite resistance; Parasites; Parasitic infection; Pathogenicity; Pathway interactions; Phenotype; Plasmodium; Plasmodium falciparum; Population; Prevention; Process; Proteins; Relapse; Resistance; Resistance development; System; Technology; Vacuole; aquaporin 3; base; combat; drug development; liver infection; malaria infection; novel strategies; novel therapeutic intervention; novel therapeutics; pressure; prevent; targeted treatment

Project Summary/Abstract Malaria remains a devastating disease in underdeveloped countries across the globe despite significant efforts to eradicate the infectious agents, unicellular parasites from the genus Plasmodium. Existing malaria therapies target the pathogenic parasites when their numbers are greatest, which creates selection pressure and hastens the development of drug resistant parasites. New therapeutic approaches are urgently needed. This project will exploit our recent discoveries about host liver cell factors essential for malaria to expand our understanding of parasitic infection and facilitate the development of novel therapeutic strategies that target host pathways. During the course of malaria infection, a precise sequence of events occurs first within human liver cells resulting in distinct morphological changes and aggressive Plasmodium replication as parasite numbers increase 10,000-fold. Also within the liver, dormant parasite forms termed hypnozoites can cause relapse months or even years after the initial infection. Both liver malaria forms remain elusive despite their significance to disease manifestation. Through an integrative approach that combines gene sequencing technologies and a forward genetic screen in Iiver cells, we discovered several human genes that are critical to Plasmodium parasite development. In particular, the host gene AQP3 (aquaporin-3) is essential for parasite viability and is up-regulated throughout the course of liver infection. AQP3 encodes an aquaglyceroporin that is generally associated with the host cell membrane. This proposal will explore the hypothesis that Plasmodium repurposes AQP3 for survival and that targeting host processes represents a strategic approach to prevent and treat malaria. We propose that the parasite hijacks AQP3 and incorporates it into the parasitophorous vacuole membrane, which surrounds the parasites. We predict that Plasmodium parasites use this protein to import essential components into the parasitophorous vacuole for proper growth and maturation. Therefore, targeting this host protein may provide a powerful and distinct approach to overcome drug resistant malaria. We will use the accessible cell-based P. berghei and P. falciparum liver stage models to track nutrients in parasite-infected cells as a function of AQP3 gene expression and protein localization. The mechanisms by which Plasmodium influences host gene expression will also be explored. Lastly, we will use chemical probes to specifically inhibit the host target to evaluate phenotypes and examine druggability. Together, these systems will expand our understanding of host-parasite interactions and allow us to evaluate host proteins as malaria drug targets to reduce resistance. !

项目概要/摘要 尽管疟疾在全球欠发达国家中仍然是一种毁灭性的疾病 努力根除疟原虫属的传染源、单细胞寄生虫。现有疟疾 当病原性寄生虫数量最多时，疗法就针对它们，这会产生选择压力 并加速耐药寄生虫的发展。迫切需要新的治疗方法。 该项目将利用我们最近关于疟疾所必需的宿主肝细胞因子的发现来扩大我们的研究范围。 了解寄生虫感染并促进针对目标的新治疗策略的开发 宿主途径。 在疟疾感染过程中，人类肝细胞内首先发生一系列精确的事件 导致明显的形态变化和寄生虫数量的侵略性疟原虫复制 增加一万倍。同样在肝脏内，称为休眠子的休眠寄生虫形式也可能导致复发 初次感染后数月甚至数年。尽管两种肝型疟疾都难以捉摸 对疾病表现的意义。通过结合基因测序的综合方法 技术和肝细胞的正向遗传筛选，我们发现了几个对 疟原虫寄生虫的发育。特别是，宿主基因 AQP3（aquaporin-3）对于寄生虫至关重要 活力，并在肝脏感染过程中上调。 AQP3 编码水甘油孔蛋白 一般与宿主细胞膜有关。 该提案将探讨疟原虫为了生存而重新利用 AQP3 的假设，以及靶向 宿主进程代表了预防和治疗疟疾的战略方法。我们建议寄生虫 劫持 AQP3 并将其整合到寄生虫周围的寄生液泡膜中。 我们预测疟原虫寄生虫利用这种蛋白质将必需成分输入到寄生体中 液泡的正常生长和成熟。因此，针对该宿主蛋白可能提供强大且 克服耐药性疟疾的独特方法。我们将使用基于细胞的 P. berghei 和 P. berghei 。 恶性疟原虫肝脏阶段模型可根据 AQP3 基因追踪寄生虫感染细胞中的营养物质 表达和蛋白质定位。疟原虫影响宿主基因表达的机制 也将被探索。最后，我们将使用化学探针特异性抑制宿主靶点来评估 表型并检查成药性。这些系统将共同扩展我们对宿主-寄生虫的理解 相互作用，使我们能够评估宿主蛋白作为疟疾药物靶点以减少耐药性。 ！

项目成果

Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death.

• DOI: 10.7554/elife.56773
• 发表时间: 2020-09-25
• 期刊: eLife
• 影响因子: 7.7
• 作者: Lu KY;Pasaje CFA;Srivastava T;Loiselle DR;Niles JC;Derbyshire E
• 通讯作者: Derbyshire E

Characterization of the Tubovesicular Network in Plasmodium vivax Liver Stage Hypnozoites and Schizonts.

• DOI: 10.3389/fcimb.2021.687019
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Sylvester K;Maher SP;Posfai D;Tran MK;Crawford MC;Vantaux A;Witkowski B;Kyle DE;Derbyshire ER
• 通讯作者: Derbyshire ER

Tafenoquine: A Step toward Malaria Elimination.

• DOI: 10.1021/acs.biochem.9b01105
• 发表时间: 2020-03-03
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Lu KY;Derbyshire ER
• 通讯作者: Derbyshire ER

Plasmodium's fight for survival: escaping elimination while acquiring nutrients.

• DOI: 10.1016/j.pt.2022.04.004
• 发表时间: 2022-07
• 期刊: TRENDS IN PARASITOLOGY
• 影响因子: 9.6
• 作者: Schroeder, Erin A.;Chirgwin, Michael E.;Derbyshire, Emily R.
• 通讯作者: Derbyshire, Emily R.