An intrinsic oscillator drives the blood stage cycle of the malaria parasite Plasmodium falciparum
Plasmodium's inner clock
Malarial fevers are notably regular, occurring when parasitized red blood cells rupture synchronously to release replicated parasites. It has long been speculated that the Plasmodium parasites that cause malaria must therefore have intrinsic circadian clocks to be able to synchronize like this. Two groups have now probed gene expression in experiments and models using data obtained during the developmental cycles of P. falciparum in vitro and in the mouse model of P. chabaudi malaria. Smith et al. discovered that four strains of P. falciparum have circadian and cell cycle oscillators, each with distinctive periodicities that can be experimentally manipulated. Rijo-Ferreira et al. found that gene expression in P. chabaudi was strikingly rhythmic, persisted during constant darkness and in infections of arrhythmic mice, and synchronized by entraining to the host's periodicity.
Abstract
The blood stage of the 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, which triggers 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 these hypotheses, we examine the P. falciparum cycle in an in vitro culture system and show that the parasite has molecular signatures associated with circadian and cell cycle oscillators. Each of the four strains examined has a different period, which indicates 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 maintains Plasmodium’s rhythmic life cycle.
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Supplementary Material
Summary
Materials and Methods
Figs. S1 to S18
Tables S1 to S8
MDAR Reproducibility Checklist
Data S1 to S4
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References and Notes
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Science
Volume 368 | Issue 6492
15 May 2020
15 May 2020
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Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 3 December 2019
Accepted: 6 April 2020
Published in print: 15 May 2020
Acknowledgments
We thank D. K. Welsh (Department of Psychiatry, University of California, San Diego) for providing us with data from the primary fibroblasts. We also thank R. Moseley and S. Campione for critical reading of the manuscript and S. Campione for technical help with figures. Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author and are not to be construed as official or as reflecting true views of the Department of the Army or the Department of Defense. Funding: F.C.M., S.B.H., J.H., A.R.L., and C.M.K. were funded by the Defense Advanced Research Projects Agency, D12AP00025. S.B.H., L.M.S., T.G., and B.C. were also funded by NIH 1R01GM126555-01. T.G. and B.C. were funded by NSF DMS-1839299. R.R.N. was funded by NIH R01 GM126555-01. S.B.H. and J.H. are members of Mimetics, LLC. J.H. is CEO of Geometric Data Analytics, Inc. T.G. and B.C. are on the board of Kanto, Inc. Author contributions: S.B.H. and J.H. conceived of the study. S.B.H., J.H., A.R.L., N.C.W., and G.C. collaborated on the experimental design. N.C.W., G.C., and J.K.M. performed parasite synchrony and release time-series experiments. A.R.L. processed samples for RNA-seq. C.M.K. designed the RNA-seq alignment and analysis pipeline and performed preliminary analyses. L.M.S. analyzed the transcriptomes for periodicity, presence of harmonics, and qualitative ordering conservation. K.E.R. developed the data-wrapping approach and assisted in period-length estimates. T.G., R.R.N., and B.C. developed the quantitative partial ordering approach and determined quantitative ordering conservation. F.C.M. constructed models of cell-to-cell variance and determined the effect on synchrony loss. L.M.S., S.B.H., F.C.M., and B.C. wrote the manuscript. Competing interests: The authors declare no competing interests. Data and materials availability: All data used in the paper are available in the supplementary materials. RNA sequences are deposited at the Gene Expression Omnibus under series GSE141653. All code used in the analyses is available in public repositories (49–51).
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