Brancucci Nicolas M B, Gerdt Joseph P, Wang ChengQi, De Niz Mariana, Philip Nisha, Adapa Swamy R, Zhang Min, Hitz Eva, Niederwieser Igor, Boltryk Sylwia D, Laffitte Marie-Claude, Clark Martha A, Grüring Christof, Ravel Deepali, Blancke Soares Alexandra, Demas Allison, Bopp Selina, Rubio-Ruiz Belén, Conejo-Garcia Ana, Wirth Dyann F, Gendaszewska-Darmach Edyta, Duraisingh Manoj T, Adams John H, Voss Till S, Waters Andrew P, Jiang Rays H Y, Clardy Jon, Marti Matthias
Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity & Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK; Harvard T.H. Chan School of Public Health, Department of Immunology and Infectious Diseases, Boston, MA 02155, USA.
Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, Boston, MA 02155, USA.
Cell. 2017 Dec 14;171(7):1532-1544.e15. doi: 10.1016/j.cell.2017.10.020. Epub 2017 Nov 9.
Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.
传播是疟原虫生命周期中的一个群体瓶颈，也是当前根除疟疾努力的关键干预目标。性别分化对于这一过程至关重要，因为只有称为配子体的有性寄生虫才能感染蚊媒。配子体的产生率因环境条件而异，但外部刺激因素仍不清楚。在这里，我们表明宿主来源的脂质溶血磷脂酰胆碱（LysoPC）通过抑制寄生虫的性别分化来控制恶性疟原虫的细胞命运。我们证明外源性LysoPC驱动必需膜成分磷脂酰胆碱的生物合成。LysoPC的限制会引发一种补偿反应，将寄生虫代谢与性阶段特异性转录的激活和配子体形成联系起来。我们的结果表明，疟原虫能够感知并处理宿主来源的生理信号以调节分化。这些数据填补了寄生虫生物学中的一个关键知识空白，并引入了疟原虫性别分化途径的一个主要组成部分，这可能为阻断疟疾传播提供新方法。
