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. !

项目总结/摘要 疟疾仍然是地球仪上不发达国家的一种毁灭性疾病， 努力根除传染源，单细胞疟原虫属寄生虫。现有疟疾 当病原性寄生虫数量最多时，治疗就针对它们，这就产生了选择压力 并加速抗药性寄生虫的发展。迫切需要新的治疗方法。 该项目将利用我们最近发现的疟疾所必需的宿主肝细胞因子， 了解寄生虫感染，促进新的治疗策略的发展， 宿主途径。 在疟疾感染的过程中，首先在人类肝细胞内发生一系列精确的事件 导致不同的形态变化和侵略性疟原虫复制作为寄生虫数量 增加了一万倍。同样在肝脏内，休眠的寄生虫形式称为催眠虫可以导致复发 几个月甚至几年后才出现。这两种肝疟疾形式仍然难以捉摸，尽管它们 对疾病表现的重要性。通过一种综合的方法， 技术和肝细胞的遗传筛查，我们发现了几个人类基因， 疟原虫寄生虫发育。特别是，宿主基因AQP 3（aquaporin-3）是寄生虫所必需的。 存活力，并在整个肝脏感染过程中上调。AQP 3编码水甘油孔蛋白， 通常与宿主细胞膜相连。 这项提议将探讨疟原虫重新利用AQP 3生存的假设， 东道方进程是预防和治疗疟疾的一种战略办法。我们认为寄生虫 劫持AQP 3并将其整合到寄生虫的空泡膜中，该空泡膜围绕寄生虫。 我们预测，疟原虫寄生虫使用这种蛋白质进口的必要成分进入寄生虫 液泡的正常生长和成熟。因此，靶向该宿主蛋白可以提供强有力的且 克服抗药性疟疾的独特方法。我们将使用可接近的细胞为基础的P. berghei和P. 一种追踪寄生虫感染细胞中营养物质作为AQP 3基因功能的恶性疟原虫肝脏阶段模型 表达和蛋白定位。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来特异性地抑制宿主靶标，以评估 表型并检查药物可药性。总之，这些系统将扩大我们对宿主-寄生虫的理解 这一发现使我们能够评估宿主蛋白质作为疟疾药物靶点以降低耐药性。 !

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

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.

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