An intrinsic oscillator drives the blood stage cycle of the malaria parasite, Plasmodium falciparum

The blood-stage infection of the malaria parasite, Plasmodium falciparum, exhibits a 48-hour developmental cycle that culminates in the synchronous release of parasites from red blood cells, triggering 48-hour fever cycles in the host. This cycle could be driven extrinsically by host circadian processes, or by a parasite-intrinsic oscillator. To distinguish between hypotheses, we examined the P. falciparum cycle in an in vitro culture system that lacks extrinsic cues from the host and show that P. falciparum has molecular signatures associated with circadian and cell-cycle oscillators. Each of four strains examined has a unique period, indicating strain-intrinsic period control. Finally, we demonstrate that parasites have low cell-to-cell variance in cycle period, on par with a circadian oscillator. We conclude that an intrinsic oscillator is responsible for Plasmodium's rhythmic life cycle. Overall design: Time-series sampling of four strains of Plasmodium falciparum cultured in vitro. Cultures were sampled every three hours for up to 69 hours, allowing capture of at least one entire developmental cycle.

恶性疟原虫（Plasmodium falciparum）的红细胞内期感染呈现48小时发育周期，最终以同步方式将寄生虫释放出红细胞，进而引发宿主出现48小时一次的发热周期。该周期既可能由宿主的昼夜节律过程外源驱动，也可能由寄生虫自身的内在振荡器调控。为区分这两种假说，我们在缺乏宿主外源信号的体外培养系统（in vitro culture system）中检测了恶性疟原虫的发育周期，证实其存在与昼夜节律振荡器（circadian oscillator）及细胞周期振荡器（cell-cycle oscillator）相关的分子特征。本次检测的4个菌株均具有各自独特的周期时长，表明周期时长由菌株内在机制调控。最后，我们证实寄生虫的周期时长在细胞间的变异程度较低，与昼夜节律振荡器的波动水平相当。综上，我们得出结论：内在振荡器是恶性疟原虫节律性生命周期的调控基础。实验总体设计：对4株体外培养的恶性疟原虫进行时序采样。培养物每3小时采样一次，最长采样时长可达69小时，足以覆盖至少一个完整的发育周期。