Defining molecular determinants of Plasmodium falciparum hematopoietic infection using single cell profiling and genetics

使用单细胞分析和遗传学定义恶性疟原虫造血系统感染的分子决定因素

• 批准号: EP/Y003705/1
• 负责人: Matthias Marti
• 金额: $ 23.84万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY003705%2F1
• 关键词: Defining; molecular; determinants; Plasmodium; falciparum

Plasmodium falciparum (Pf) malaria remains a leading cause of death in many low- and middle-income countries, particularly in Sub-Saharan Africa. Further exploration into uncharacterized areas of parasite biology within the human host is essential for identifying novel avenues for antimalarial therapies, transmission-blocking strategies, and/or diagnostics aimed at reducing the global disease burden. Recent work has identified the hematopoietic niches of the bone and spleen as major sites of Pf parasite replication and development. Importantly, these organs serve both as extravascular reservoirs for asexual blood-stage parasites that cause clinical symptoms of malaria, and as sites for development of gametocytes, sexual stages that are required for transmission between human hosts. Nonetheless, the relative inaccessibility of these organs in humans and their highly heterogenous composition has impeded our understanding of the mechanisms underlying parasite replication and differentiation within these niches. Blood-stage parasites also have the capacity to invade erythrocytes of various maturation states, further contributing to the heterogeneity of infection within the hematopoietic niche. Single cell methods provide unprecedented opportunities to investigate these complex processes at exceptionally high resolution. Here, I propose to leverage these technologies, in combination with reverse genetics, to dissect the respective contributions of host cell-intrinsic and -extrinsic factors to parasite development in the hematopoietic niche. I hypothesize that Pf blood-stage parasites transcriptionally adapt both to their external organ environment and to their specific host cell, leading to major changes in parasite biology that can drive pathology, impact transmission, and affect antimalarial drug responses.

在许多低收入国家和撒哈拉以南非洲，恶性疟原虫（PF）疟疾仍然是死亡的主要原因。进一步探索人类宿主中寄生虫生物学的未表征区域对于鉴定抗疟疾疗法，传播阻断策略和/或旨在减轻全球疾病负担的新型途径至关重要。最近的工作已经确定骨骼和脾脏的造血小裂是PF寄生虫复制和发育的主要部位。重要的是，这些器官既是引起疟疾临床症状的无性血液阶段寄生虫的血管外储层，又是用于疟疾的临床症状的，是配子细胞发展的地点，是人类宿主之间传播所需的性阶段。尽管如此，这些器官在人类及其高度异质组成的相对无法获得性阻碍了我们对这些壁ches中寄生虫复制和分化的机制的理解。血级寄生虫还具有侵入各种成熟态的红细胞的能力，进一步导致造血生态位感染的异质性。单细胞方法提供了前所未有的机会，可以在异常高的分辨率下研究这些复杂的过程。在这里，我建议利用这些技术与反向遗传学相结合，以剖析宿主细胞中性和 - 超级因子对造血生态位的寄生虫发育的各自贡献。我假设PF血液阶段寄生虫在转录上既适应其外部器官环境又适应其特定宿主细胞，从而导致寄生虫生物学的重大变化，这些变化可以推动病理学，影响传播并影响抗疟药药物反应。