Uncovering the parasite and host determinants of Plasmodium vivax hypnozoite formation and development using single cell sequencing and human liver-chimeric mice

利用单细胞测序和人肝嵌合小鼠揭示间日疟原虫休眠子形成和发育的寄生虫和宿主决定因素

• 批准号: 10452314
• 负责人: Ashley M Vaughan
• 金额: $ 94.67万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-07 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10452314
• 关键词: Address; Africa; Aminoquinolines; Antimalarials; Area; Asia; Biological; Biological Assay; Biology; Birth Weight; Bite; Blood; Cell Separation; Cells; Central America; Chromatin; Climate; Clinical; Culicidae; Development; Disease; Erythrocytes; Frequencies; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Geography; Glucosephosphate Dehydrogenase Deficiency; Half-Life; Health; Hepatocyte; Horns; Host Defense; Human; Immunofluorescence Immunologic; Individual; Infant Mortality; Infection; Intervention; Intrinsic factor; Invaded; Investigation; Knowledge; Lead; Life Cycle Stages; Link; Liver; Malaria; Methods; Modeling; Morbidity - disease rate; Mus; Oceania; Parasites; Pathway interactions; Persons; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Population; Pregnant Women; Primaquine; Process; Proteins; RNA; Regimen; Relapse; Research; Residencies; Seeds; South America; Sporozoites; Stimulus; Testing; climate zone; combat; cost; dosage; drug standard; early pregnancy loss; improved; in vivo; in vivo Model; infection risk; innovation; insight; knock-down; malaria infection; mouse model; negative affect; next generation; novel; prevent; single cell analysis; single cell sequencing; spatiotemporal; transcriptomics; transmission process

The human malaria-causing parasite Plasmodium vivax is geographically the most widespread of all the Plasmodium species. P. vivax is a major cause of morbidity in endemic regions of Asia, Oceania, Central and South America, as well as the horn of Africa. In these regions, P. vivax infections in pregnant women significantly contribute to early pregnancy loss, reduced birth weight and infant mortality. Notably, P. vivax is a major concern in an arena of malaria eradication due to its unique biology. Specifically, P. vivax sporozoite infectivity of hepatocytes does not always lead to the onset of schizogony and transition to blood stage disease, as is the case for P. falciparum. Rather, a sporozoite can enter a host hepatocyte, dedifferentiate and then lie dormant within the host hepatocyte for weeks, months or even years, before reactivating. This dormant or latent liver stage form is known as the hypnozoite and in continued efforts towards malaria elimination and eradication, the hypnozoite is a formidable foe. Indeed, the endemicity of P. vivax throughout tropical as well as temperate climate zones is attributed to the parasite’s ability to form hypnozoites, which after reactivating, case relapses of blood stage infection and concomitant transmission. Antimalarial drugs almost exclusively target the symptomatic blood stage of the life cycle and do not target the hypnozoite and thus treatment of P. vivax blood stage infections with standard drug regimens allows for further relapses and will not aid in disease eradication. Historically, the only approved drug active against P. vivax hypnozoites was primaquine although an improved 8-aminoquinoline drug, tafenoquine, has recently received approval for the treatment of relapsing malaria. Unfortunately, primaquine’s short half-life, long dosage regimen and incompatibility with glucose-6- phosphate dehydrogenase deficiency, prevent its use for mass elimination campaigns. Thus, there is a need for novel interventions that will negatively affect hypnozoite formation, survival and relapse. Thus, the research in this proposal aims to shed biological insight on the hypnozoite. This application aims to address three critical biological questions pertaining to P. vivax hypnozoite biology and answering these questions should aid in the discovery of novel interventions to prevent hypnozoite relapse and the continued spread of P. vivax disease. Specifically, are there intrinsic factors that are pre-programmed in the P. vivax sporozoite that determine its fate once it reaches the liver to become either a replicating schizont or a dormant hypnozoite? How does the dormant hypnozoite manipulate its host cell in order to maintain its long-term residency? Can we develop a model of hypnozoite relapse in order to gain insight into the triggers that promote hypnozoite reactivation? Using a human-liver chimeric mouse model alongside innovative methods of single cell isolation and transcriptional profiling, we hope to being to address these challenges.

引起人类疟疾的寄生虫疟原虫在地理上是所有人中最广泛的 疟原虫物种。 Vivax是亚洲流行地区发病率的主要原因，大洋洲， 中美洲和南美以及非洲之角。在这些区域，孕妇的疟原虫感染 妇女显着促进早期妊娠损失，减轻出生体重和婴儿死亡率。值得注意的是，P。 Vivax由于其独特的生物学而在消除疟疾的舞台上是一个主要问题。具体来说，vivax 肝细胞的孢子岩感染并不总是导致精神分裂的发作和过渡到血液 舞台疾病，恶性疟原虫也是如此。相反，子孢子可以进入宿主肝细胞， 去分化，然后在宿主肝细胞中处于休眠状态数周，几个月甚至几年之前 重新激活。这种休眠或潜在的肝脏阶段形式被称为催眠症，在继续努力中 消除疟疾，催眠症是强大的敌人。确实，P。 在整个热带和温度气候区域中的Vivax归因于寄生虫形成的能力 在重新激活后，血液阶段感染和伴随传播的病例继电器。 抗疟药几乎仅针对生命周期的有症状血液阶段，而不针对 用标准药物方案治疗催眠症状，从而治疗腹地疟原虫的血液阶段感染允许 进一步的继电器，不会有助于消除疾病。 从历史上看，唯一的针对维瓦克斯催眠症状的批准的药物是primaquine，尽管是 改进的8-氨基喹啉药物Tafenoquine最近获得了接力的批准 疟疾。不幸的是，Primaquine的半衰期，长剂量方案和与葡萄糖6--的不相容性 磷酸盐脱氢酶缺乏症，防止其用于消除质量的运动。那有一个 需要对新的干预措施产生负面影响的新干预措施，从而影响催眠症症状的形成，生存和救济。那， 该提案中的研究旨在使生物学见解催眠症。该应用程序旨在解决 与Vivax Hypnozoite生物学有关的三个关键生物学问题并回答这些问题 应该有助于发现新的干预措施，以防止催眠后继电器并继续传播 P. Vivax疾病。 具体而言，是否存在固有因素，这些因素是在葡萄球菌孢子岩中预先编程的 一旦到达肝脏就可以成为复制的精神分裂症或休眠的催眠症？ 休眠的催眠症如何操纵其宿主细胞以维持其长期的沉积物？能 我们开发了催眠岩继电器的模型，以深入了解促进催眠症的触发因素 重新激活？使用人肝小鼠模型以及单细胞的创新方法 隔离和转录分析，我们希望能够解决这些挑战。