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

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. Access

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SIMILAR CONTENT BEING VIEWED BY OTHERS _PLASMODIUM FALCIPARUM_ TRANSCRIPTION IN DIFFERENT CLINICAL PRESENTATIONS OF MALARIA ASSOCIATES WITH CIRCULATION TIME OF INFECTED ERYTHROCYTES Article

Open access 30 July 2021 GENE EXPRESSION ANALYSES REVEAL DIFFERENCES IN CHILDREN’S RESPONSE TO MALARIA ACCORDING TO THEIR AGE Article Open access 06 March 2024 GENOME-WIDE GENE EXPRESSION

PROFILES THROUGHOUT HUMAN MALARIA PARASITE LIVER STAGE DEVELOPMENT IN HUMANIZED MICE Article Open access 31 January 2025 ACCESSION CODES PRIMARY ACCESSIONS GENE EXPRESSION OMNIBUS * GSE9152

DATA DEPOSITS The array data are deposited in the Gene Expression Omnibus under accession number GSE9152. REFERENCES * White, N. in _Manson’s Tropical Diseases_ 21st edn (eds Cook, G. C.

& Zumla, A. I.) 1205–1295 (Elsevier Science and W. B. Saunders, Edinburgh, 2002) Google Scholar  * Greenwood, B., Marsh, K. & Snow, R. Why do some African children develop severe

malaria? _Parasitol. Today_ 7, 277–281 (1991) Article  CAS  Google Scholar  * Llinas, M., Bozdech, Z., Wong, E. D., Adai, A. T. & DeRisi, J. L. Comparative whole genome transcriptome

analysis of three _Plasmodium falciparum_ strains. _Nucleic Acids Res._ 34, 1166–1173 (2006) Article  CAS  Google Scholar  * Daily, J. P. et al. _In vivo_ transcriptional profiling of _P. _

_falciparum_ . _Malar. J._ 3, 30 (2004) Article  Google Scholar  * Daily, J. P. et al. _In vivo_ transcriptome of _Plasmodium falciparum_ reveals overexpression of transcripts that encode

surface proteins. _J. Infect. Dis._ 191, 1196–1203 (2005) Article  CAS  Google Scholar  * Brunet, J. P., Tamayo, P., Golub, T. R. & Mesirov, J. P. Metagenes and molecular pattern

discovery using matrix factorization. _Proc. Natl Acad. Sci. USA_ 101, 4164–4169 (2004) Article  CAS  ADS  Google Scholar  * Le Roch, K. G. et al. Discovery of gene function by expression

profiling of the malaria parasite life cycle. _Science_ 301, 1503–1508 (2003) Article  CAS  ADS  Google Scholar  * Bozdech, Z. et al. The transcriptome of the intraerythrocytic developmental

cycle of _Plasmodium falciparum_ . _PLoS Biol._ 1, E5 (2003) Article  Google Scholar  * Young, J. A. et al. The _Plasmodium falciparum_ sexual development transcriptome: a microarray

analysis using ontology-based pattern identification. _Mol. Biochem. Parasitol._ 143, 67–79 (2005) Article  CAS  Google Scholar  * Subramanian, A. et al. Gene set enrichment analysis: a

knowledge-based approach for interpreting genome-wide expression profiles. _Proc. Natl Acad. Sci. USA_ 102, 15545–15550 (2005) Article  CAS  ADS  Google Scholar  * Hansen, M., Kun, J. F.,

Schultz, J. E. & Beitz, E. A single, bi-functional aquaglyceroporin in blood-stage _Plasmodium falciparum_ malaria parasites. _J. Biol. Chem._ 277, 4874–4882 (2002) Article  CAS  Google

Scholar  * Promeneur, D. et al. Aquaglyceroporin PbAQP during intraerythrocytic development of the malaria parasite _Plasmodium berghei_ . _Proc. Natl Acad. Sci. USA_ 104, 2211–2216 (2007)

Article  CAS  ADS  Google Scholar  * Yeh, I., Hanekamp, T., Tsoka, S., Karp, P. D. & Altman, R. B. Computational analysis of _Plasmodium falciparum_ metabolism: organizing genomic

information to facilitate drug discovery. _Genome Res._ 14, 917–924 (2004) Article  CAS  Google Scholar  * Lang-Unnasch, N. & Murphy, A. D. Metabolic changes of the malaria parasite

during the transition from the human to the mosquito host. _Annu. Rev. Microbiol._ 52, 561–590 (1998) Article  CAS  Google Scholar  * Uyemura, S. A., Luo, S., Vieira, M., Moreno, S. N. &

Docampo, R. Oxidative phosphorylation and rotenone-insensitive malate- and NADH-quinone oxidoreductases in _Plasmodium yoelii yoelii_ mitochondria _in situ_ . _J. Biol. Chem._ 279, 385–393

(2004) Article  CAS  Google Scholar  * Tsai, A. G., Johnson, P. C. & Intaglietta, M. Oxygen gradients in the microcirculation. _Physiol. Rev._ 83, 933–963 (2003) Article  CAS  Google

Scholar  * Planche, T. & Krishna, S. Severe malaria: metabolic complications. _Curr. Mol. Med._ 6, 141–153 (2006) Article  CAS  Google Scholar  * Ockenhouse, C. F. et al. Common and

divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria. _Infect. Immun._ 74,

5561–5573 (2006) Article  CAS  Google Scholar  * Lyke, K. E. et al. Serum levels of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, IL-8, IL-10, tumor necrosis factor α, and

IL-12(p70) in Malian children with severe _Plasmodium falciparum_ malaria and matched uncomplicated malaria or healthy controls. _Infect. Immun._ 72, 5630–5637 (2004) Article  CAS  Google

Scholar  * Udomsangpetch, R. et al. Febrile temperatures induce cytoadherence of ring-stage _Plasmodium falciparum_-infected erythrocytes. _Proc. Natl Acad. Sci. USA_ 99, 11825–11829 (2002)

Article  CAS  ADS  Google Scholar  * Olesen, J., Hahn, S. & Guarente, L. Yeast HAP2 and HAP3 activators both bind to the CYC1 upstream activation site, UAS2, in an interdependent manner.

_Cell_ 51, 953–961 (1987) Article  CAS  Google Scholar  * Becker, D. M., Fikes, J. D. & Guarente, L. A cDNA encoding a human CCAAT-binding protein cloned by functional complementation

in yeast. _Proc. Natl Acad. Sci. USA_ 88, 1968–1972 (1991) Article  CAS  ADS  Google Scholar  * Krungkrai, J., Prapunwattana, P. & Krungkrai, S. R. Ultrastructure and function of

mitochondria in gametocytic stage of _Plasmodium falciparum_ . _Parasite_ 7, 19–26 (2000) Article  CAS  Google Scholar  * Mahan, M. J., Slauch, J. M. & Mekalanos, J. J. Selection of

bacterial virulence genes that are specifically induced in host tissues. _Science_ 259, 686–688 (1993) Article  CAS  ADS  Google Scholar  * Tamayo, P. et al. Metagene projection for

cross-platform, cross-species characterization of global transcriptional states. _Proc. Natl Acad. Sci. USA_ 104, 5959–5964 (2007) Article  CAS  ADS  Google Scholar  * Marion, R. M. et al.

Sfp1 is a stress- and nutrient-sensitive regulator of ribosomal protein gene expression. _Proc. Natl Acad. Sci. USA_ 101, 14315–14322 (2004) Article  CAS  ADS  Google Scholar  * Faye, O. et

al. Comparison of the transmission of malaria in 2 epidemiological patterns in Senegal: the Sahel border and the Sudan-type savanna. _Dakar Med._ 40, 201–207 (1995) CAS  PubMed  Google

Scholar  * Zhou, Y. & Abagyan, R. Match-Only Integral Distribution (MOID) algorithm for high-density oligonucleotide array analysis. _BMC Bioinformatics_ 3, 3 (2002) Article  Google

Scholar  * Reich, M. et al. GenePattern 2.0. _Nature Genet._ 38, 500–501 (2006) Article  CAS  Google Scholar  * Kanehisa, M. A database for post-genome analysis. _Trends Genet._ 13, 375–376

(1997) Article  CAS  Google Scholar  * Ginsburg, H. Progress in _in silico_ functional genomics: the Malaria Metabolic Pathways database. _Trends Parasitol._ 22, 238–240 (2006) Article  CAS

  Google Scholar  * Bahl, A. et al. PlasmoDB: the _Plasmodium_ genome resource. A database integrating experimental and computational data. _Nucleic Acids Res._ 31, 212–215 (2003) Article 

CAS  Google Scholar  * Zhou, Y. et al. _In silico_ gene function prediction using ontology-based pattern identification. _Bioinformatics_ 21, 1237–1245 (2005) Article  Google Scholar  *

Segal, E., Friedman, N., Koller, D. & Regev, A. A module map showing conditional activity of expression modules in cancer. _Nature Genet._ 36, 1090–1098 (2004) Article  CAS  Google

Scholar  * Ashburner, M., Mungall, C. J. & Lewis, S. E. Ontologies for biologists: a community model for the annotation of genomic data. _Cold Spring Harb. Symp. Quant. Biol._ 68,

227–235 (2003) Article  CAS  Google Scholar  * Karp, P. D. et al. Expansion of the BioCyc collection of pathway/genome databases to 160 genomes. _Nucleic Acids Res._ 33, 6083–6089 (2005)

Article  CAS  Google Scholar  * Mewes, H. W. et al. MIPS: analysis and annotation of proteins from whole genomes in 2005. _Nucleic Acids Res._ 34, D169–D172 (2006) Article  CAS  Google

Scholar  * Harbison, C. T. et al. Transcriptional regulatory code of a eukaryotic genome. _Nature_ 431, 99–104 (2004) Article  CAS  ADS  Google Scholar  * Gerber, A. P., Herschlag, D. &

Brown, P. O. Extensive association of functionally and cytotopically related mRNAs with Puf family RNA-binding proteins in yeast. _PLoS Biol._ 2, E79 (2004) Article  Google Scholar  *

Snounou, G. et al. Biased distribution of _msp1_ and _msp2_ allelic variants in _Plasmodium falciparum_ populations in Thailand. _Trans. R. Soc. Trop. Med. Hyg._ 93, 369–374 (1999) Article 

CAS  Google Scholar  * Happi, C. T. et al. Molecular analysis of _Plasmodium falciparum_ recrudescent malaria infections in children treated with chloroquine in Nigeria. _Am. J. Trop. Med.

Hyg._ 70, 20–26 (2004) Article  CAS  Google Scholar  Download references 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 * J. P. Mesirov and A. Regev: These authors contributed equally to this

work. AUTHORS AND AFFILIATIONS * Department of Immunology and Infectious Disease,, J. P. Daily, K. Levasseur, C. Dong & D. Wirth * Department of Biostatistics, Harvard School of Public

Health, 665 Huntington Avenue, Boston, Massachusetts 02115, USA, D. Wypij * Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA, J. P.

Daily * 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 * FAS Center for Systems Biology, Harvard University, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA , N. Pochet *

Department of Cell Biology and Neuroscience, 900 University Avenue, University of California, Riverside, California 92521, USA, K. Le Roch * Genomics Institute of the Novartis Research

Foundation, San Diego, California 92121, USA , D. Plouffe, Y. Zhou & E. A. Winzeler * Laboratory of Bacteriology and Virology,, O. Sarr & S. Mboup * Department of Parasitology and

Mycology, Dantec Hospital, Cheikh Anta Diop University, Dakar, BP 5005, Senegal, O. Ndir & D. Ndiaye * Department of Biology, Massachusetts Institute of Technology, 31 Ames Street,

Cambridge, Massachusetts 02139, USA, E. S. Lander & A. Regev * The Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA , E. S. Lander

* Department of Cell Biology, The Scripps Research Institute, 10550 Torrey Pines Road, La Jolla, California 92037, USA, E. A. Winzeler Authors * J. P. Daily View author publications You can

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Regev. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION The file contains Legends to Supplementary Figures 1-7 and Supplementary Tables 1-8; Supplementary Notes 1-2; Supplementary Figures

1-5 and 7; Supplementary Tables 1-4 and 7. (PDF 10117 kb) SUPPLEMENTARY TABLE 5 This file contains Supplementary Table 5. (XLS 11 kb) SUPPLEMENTARY TABLE 6 This file contains Supplementary

Table 6. (XLS 108 kb) SUPPLEMENTARY TABLE 8 This file contains Supplementary Table 8. (XLS 52 kb) SUPPLEMENTARY FIGURE 6 This file contains Supplementary Figure 6. (PDF 30965 kb) RIGHTS AND

PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 17 May 2007 * Accepted: 26 September 2007 * Published: 28

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