1. Department of Immunology and Infectious Disease,
2. Department of Biostatistics, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA
3. Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA
4. Broad Institute of Massachusetts Institute of Technology and Harvard University, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA
5. FAS Center for Systems Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA
6. Department of Cell Biology and Neuroscience, 900 University Avenue, University of California, Riverside, California 92521, USA
7. Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA
8. Laboratory of Bacteriology and Virology,
9. Department of Parasitology and Mycology, Dantec Hospital, Cheikh Anta Diop University, Dakar, BP 5005, Senegal
10. Department of Biology, Massachusetts Institute of Technology, 31 Ames Street, Cambridge, Massachusetts 02139, USA
11. The Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA
12. Department of Cell Biology, The Scripps Research Institute, 10550 Torrey Pines Road, La Jolla, California 92037, USA
13. These authors contributed equally to this work.

Correspondence to: J. P. Mesirov^4,13A. Regev^4,10,13 Correspondence and requests for materials should be addressed to J.P.M. (Email: mesirov@broad.mit.edu) or A.R. (Email: aregev@broad.mit.edu).

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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