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

恶性疟仍是许多低收入和中等收入国家的主要死亡原因，尤其是在撒哈拉以南非洲。进一步探索人类宿主内寄生虫生物学的未知领域，对于确定旨在减轻全球疾病负担的抗疟疾治疗、传播阻断战略和/或诊断的新途径至关重要。最近的工作已经确定，骨骼和脾的造血龛是PF寄生虫复制和发展的主要部位。重要的是，这些器官既是引起疟疾临床症状的无性血液期寄生虫的血管外储存库，也是配子体发育的场所，配子体是在人类宿主之间传播所需的有性阶段。然而，这些器官在人类体内的相对不可及及其高度异质性的组成阻碍了我们对这些利基内寄生虫复制和分化的潜在机制的理解。血液期寄生虫还具有侵入不同成熟状态的红细胞的能力，进一步促进了造血生态位内感染的异质性。单细胞方法提供了前所未有的机会，以极高的分辨率研究这些复杂的过程。在这里，我建议利用这些技术，结合反向遗传学，剖析宿主细胞内在和外在因素对造血生态位中寄生虫发育的各自贡献。我假设PF血液期寄生虫在转录上适应它们的外部器官环境和特定的宿主细胞，导致寄生虫生物学上的重大变化，这些变化可以驱动病理，影响传播，并影响抗疟疾药物的反应。

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.