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Distinct physiological states of Plasmodium falciparum in malaria-infected patients

Nature volume 450, pages 1091–1095 (2007)Cite this article

Abstract

Infection with the malaria parasite Plasmodium falciparum leads to widely different clinical conditions in children, ranging from mild flu-like symptoms to coma and death1. Despite the immense medical implications, the genetic and molecular basis of this diversity remains largely unknown2. Studies of in vitro gene expression have found few transcriptional differences between different parasite strains3. Here we present a large study of in vivo expression profiles of parasites derived directly from blood samples from infected patients. The in vivo expression profiles define three distinct transcriptional states. The biological basis of these states can be interpreted by comparison with an extensive compendium of expression data in the yeast Saccharomyces cerevisiae. The three states in vivo closely resemble, first, active growth based on glycolytic metabolism, second, a starvation response accompanied by metabolism of alternative carbon sources, and third, an environmental stress response. The glycolytic state is highly similar to the known profile of the ring stage in vitro, but the other states have not been observed in vitro. The results reveal a previously unknown physiological diversity in the in vivo biology of the malaria parasite, in particular evidence for a functional mitochondrion in the asexual-stage parasite, and indicate in vivo and in vitro studies to determine how this variation may affect disease manifestations and treatment.

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Figure 1: P. falciparum expression profiles in vivo.
Figure 2: Physiological characterization of Plasmodium profiles by cross-species projection.
Figure 3: Gene-set enrichment analysis of P. falciparum clusters.
Figure 4: Induction of respiratory metabolism and repression of glycolysis in cluster 1 versus cluster 2.
Figure 5: Expression of glycolysis, tricarboxylic acid cycle and fatty acid metabolism genes in clusters 1 and 2.

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Gene Expression Omnibus

Data deposits

The array data are deposited in the Gene Expression Omnibus under accession number GSE9152.

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Acknowledgements

We thank the villagers and health care workers in Velingara, Senegal, for their participation in and support of this project; T. Taylor for critical advice and encouragement; G. Chechik, N. Barkai and O. Rando for providing parts of the compiled expression compendium for S. cerevisiae; and J. Bistline for assistance with the figures. J.P.D. is supported by the National Institute of Allergy and Infectious Diseases. N.P. is a Henri Benedictus Fellow of the King Baudouin Foundation and the Belgian American Educational Foundation. P.T. is supported by the National Institutes of Health (NIH). D.F.W. is supported by the Ellison Medical Foundation, the NIH, the Exxon Mobil Foundation and the Harvard School of Public Health. E.A.W. is supported by the Keck Foundation, the Novartis Research Foundation and the NIH. J.P.M. and D.S. are supported by the NIH and the National Science Foundation. A.R. is supported by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund. The field work was supported by the Fogarty International from the NIH, the NIH Malaria Diversity grant, the Exxon Mobil Foundation, the Ellison Medical Foundation, the Burroughs–Welcome Fund and the Broad Institute of MIT and Harvard.

Author Contributions. D.S., N.P. and K.L.R. contributed equally to this work.

Author information

Author notes

  1. J. P. Mesirov and A. Regev: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology and Infectious Disease,,

    J. P. Daily, K. Levasseur, C. Dong & D. Wirth

  2. Department of Biostatistics, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA,

    D. Wypij

  3. Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA,

    J. P. Daily

  4. Broad Institute of Massachusetts Institute of Technology and Harvard University, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA ,

    D. Scanfeld, N. Pochet, M. Kamal, E. Thomas, P. Tamayo, E. S. Lander, J. P. Mesirov & A. Regev

  5. FAS Center for Systems Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA ,

    N. Pochet

  6. Department of Cell Biology and Neuroscience, 900 University Avenue, University of California, Riverside, California 92521, USA,

    K. Le Roch

  7. Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA ,

    D. Plouffe, Y. Zhou & E. A. Winzeler

  8. Laboratory of Bacteriology and Virology,,

    O. Sarr & S. Mboup

  9. Department of Parasitology and Mycology, Dantec Hospital, Cheikh Anta Diop University, Dakar, BP 5005, Senegal,

    O. Ndir & D. Ndiaye

  10. Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, Massachusetts 02139, USA,

    E. S. Lander & A. Regev

  11. The Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA ,

    E. S. Lander

  12. Department of Cell Biology, The Scripps Research Institute, 10550 Torrey Pines Road, La Jolla, California 92037, USA,

    E. A. Winzeler

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Corresponding authors

Correspondence to J. P. Mesirov or A. Regev.

Supplementary information

Supplementary Information

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Daily, J., Scanfeld, D., Pochet, N. et al. Distinct physiological states of Plasmodium falciparum in malaria-infected patients. Nature 450, 1091–1095 (2007). https://doi.org/10.1038/nature06311

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