Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum.
Phenotypic Screens Identify Genetic Factors Associated with Gametocyte Development in the Human Malaria Parasite Plasmodium falciparum.
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表型筛选鉴定与人类疟原虫恶性疟原虫配子体发育相关的遗传因素。
DOI：
10.1128/spectrum.04164-22
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发表时间：
2023-06-15
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
致命的疟原虫恶性疟原虫从人类传播到蚊子是通过称为配子细胞的特殊红细胞内有性形式实现的。尽管导致配子细胞定型的关键调节机制最近已被揭示，但控制性发育的基因网络仍有待阐明。在这里，我们报告了一个混合突变体筛选，以鉴定与恶性疟原虫配子体发育相关的基因。我们的结果将调节配子体进展的基因分类为配子体生产不足或生产过多的基因，并且对个体克隆的深入分析证实了性承诺率的表型和配子体发育中的推定功能。我们提出了一组以前未涉及配子细胞发生的新基因，并证明了正向遗传筛选在分离影响寄生虫性生物学的基因方面的潜力，这是朝着发现全球重要病原体的新抗疟药迈出的令人兴奋的一步。重要性 阻断人传病媒介传播是消除疟疾的重要一步。配子体完全负责实现这种传递，并代表了治疗干预的机会。虽然这些镰状寄生虫阶段首次在 1880 年代被发现，但我们对导致其形成的遗传决定因素以及驱动其发育的分子机制的了解有限。在这项工作中，我们开发了一种可扩展的piggyBac突变体筛选方法，以鉴定影响最致命的人类疟原虫恶性疟原虫配子体发育的基因。通过这样做，我们为大规模功能基因组研究奠定了基础，该研究专门用于解决有关恶性疟原虫的性承诺、成熟和蚊子感染的剩余问题。这种功能性遗传筛选将有助于加快识别开发新型传播阻断剂的基本途径和过程。
Transmission of the deadly malaria parasite Plasmodium falciparum from humans to mosquitoes is achieved by specialized intraerythrocytic sexual forms called gametocytes. Though the crucial regulatory mechanisms leading to gametocyte commitment have recently come to light, networks of genes that control sexual development remain to be elucidated. Here, we report a pooled-mutant screen to identify genes associated with gametocyte development in P. falciparum. Our results categorized genes that modulate gametocyte progression as hypoproducers or hyperproducers of gametocytes, and the in-depth analysis of individual clones confirmed phenotypes in sexual commitment rates and putative functions in gametocyte development. We present a new set of genes that have not been implicated in gametocytogenesis before and demonstrate the potential of forward genetic screens in isolating genes impacting parasite sexual biology, an exciting step toward the discovery of new antimalarials for a globally significant pathogen. IMPORTANCE Blocking human-to-vector transmission is an essential step toward malaria elimination. Gametocytes are solely responsible for achieving this transmission and represent an opportunity for therapeutic intervention. While these falciform-shaped parasite stages were first discovered in the 1880s, our understanding of the genetic determinants responsible for their formation and molecular mechanisms that drive their development is limited. In this work, we developed a scalable screening methodology with piggyBac mutants to identify genes that influence the development of gametocytes in the most lethal human malaria parasite, P. falciparum. By doing so, we lay the foundation for large-scale functional genomic studies specifically designed to address remaining questions about sexual commitment, maturation, and mosquito infection in P. falciparum. Such functional genetic screens will serve to expedite the identification of essential pathways and processes for the development of novel transmission-blocking agents.
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