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. !

项目摘要/摘要 尽管巨大 消除传染剂的努力，质子属的单细胞寄生虫。现有的疟疾 当疗法数量最大时，靶向致病寄生虫，这会产生选择压力 并加快耐药寄生虫的发展。迫切需要新的治疗方法。 该项目将利用我们最近关于宿主肝细胞因素的发现，使疟疾扩展我们 了解寄生虫感染并促进针对性的新型治疗策略的发展 主机路径。 在疟疾感染过程中，人肝细胞中首先发生了精确的事件序列 导致明显的形态变化和攻击性质量复制作为寄生虫数 增加10,000倍。同样在肝脏内，休眠的​​寄生虫形式称为催眠症，可能导致复发 初期感染后的几个月甚至几年。两种肝疟疾形式仍然难以捉摸 对疾病表现的意义。通过结合基因测序的综合方法 技术和iiver细胞中的远期遗传筛选，我们发现了几个对 疟原虫发育。特别是，宿主基因AQP3（Aquaporin-3）对于寄生虫至关重要 生存能力，并在整个肝感染过程中被上调。 AQP3编码一个水甘油烯烃 通常与宿主细胞膜有关。 该提案将探讨以下假设：疟原虫重新利用AQP3以生存和靶向 宿主过程代表了一种预防和治疗疟疾的战略方法。我们建议寄生虫 劫持AQP3，并将其掺入寄生虫的寄生虫液泡膜中。 我们预测疟原虫使用该蛋白将必需成分进口到寄生虫中 液泡以适当的生长和成熟。因此，靶向该宿主蛋白可能会提供强大的和 克服耐药性疟疾的独特方法。我们将使用可访问的基于细胞的P. Berghei和P. 恶性肝阶段模型以跟踪寄生虫感染细胞中的养分随着AQP3基因的函数 表达和蛋白质定位。疟原虫影响宿主基因表达的机制 也将探索。最后，我们将使用化学探针专门抑制宿主目标以评估 表型并检查可药物。这些系统将共同扩展我们对宿主寄生虫的理解 相互作用并允许我们评估宿主蛋白作为疟疾药物靶标，以降低耐药性。 呢

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