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Transcriptional profiling of growth perturbations of the human malaria parasite Plasmodium falciparum

Nature Biotechnology volume 28, pages 9198 (2010) | Download Citation

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Abstract

Functions have yet to be defined for the majority of genes of Plasmodium falciparum, the agent responsible for the most serious form of human malaria. Here we report changes in P. falciparum gene expression induced by 20 compounds that inhibit growth of the schizont stage of the intraerythrocytic development cycle. In contrast with previous studies, which reported only minimal changes in response to chemically induced perturbations of P. falciparum growth, we find that 59% of its coding genes display over three-fold changes in expression in response to at least one of the chemicals we tested. We use this compendium for guilt-by-association prediction of protein function using an interaction network constructed from gene co-expression, sequence homology, domain-domain and yeast two-hybrid data. The subcellular localizations of 31 of 42 proteins linked with merozoite invasion is consistent with their role in this process, a key target for malaria control. Our network may facilitate identification of novel antimalarial drugs and vaccines.

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Acknowledgements

This project was funded by the Academic Research Council of the Singapore Ministry of Education (grant no. ARC 11/05 M45080011), Singaporean National Medical Research Council (grant # IRG07Nov030) and the Deutsche Forschungsgemeinschaft (GI312 and GRK1459). The authors also thank B.D. Wastuwidyaningtyas and S. Tan for excellent technical assistance with the microarray experiments, K. Jurries for graphical assistance and A. Law, R. Stanway, T. Voss and H. Hoppe for critical reading of the manuscript. We are grateful to M. Blackman (National Institute for Medical Research, London) for providing the MSP-1 antibody, to P. Sharma (National Institute of Immunology, New Delhi) for providing the GAP45 antibody and to Jacobus Pharmaceuticals for providing WR99210.

Author information

Author notes

    • Guangan Hu
    •  & Ana Cabrera

    These authors contributed equally to this work.

Affiliations

  1. Division of Genetics and Genomics, School of Biological Sciences, Nanyang Technological University, Singapore.

    • Guangan Hu
    • , Sachel Mok
    • , Balbir K Chaal
    • , Sabna Cheemadan
    • , Peter R Preiser
    •  & Zbynek Bozdech
  2. Bernhard Nocht Institute for Tropical Medicine, Department of Molecular Parasitology, Hamburg, Germany.

    • Ana Cabrera
    • , Maya Kono
    • , Silvia Haase
    • , Klemens Engelberg
    • , Tobias Spielmann
    •  & Tim-W Gilberger

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Contributions

G.H. and Z.B. performed the computation and data analysis. G.H., A.C., P.R.P., T.S., T.-W.G. and Z.B. drafted the paper. S.M., G.H., S.C. and B.K.C. performed the microarray experiments. A.C., M.K., S.H., K.E. and T.S. cloned the genes, generated the transgenic parasites and carried out the microscopy. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Tim-W Gilberger or Zbynek Bozdech.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figs. 1–7 and Supplementary Tables 1,3,7

Excel files

  1. 1.

    Supplementary Table 2

    Raw data from microarray based perturbations analyses (Supplementary File 1 online).

  2. 2.

    Supplementary Table 4

    Results of the MLC module analyses of the 90% confidence network (Supplementary File 2 online).

  3. 3.

    Supplementary Table 5

    Functional predictions of P. falciparum genes by WNC using the 50% confidence network (Supplementary File 3 online).

  4. 4.

    Supplementary Table 6

    Genes assigned to the merozoite invasion sub-network (Supplementary File 4 online).

Videos

  1. 1.

    Supplementary Movie 1

    MAL13P1.130-GFP localization in early schizonts. 360°C rotation of a 3-dimensional representation of a live cell was generated from an early shizont stage parasite as described in Figure 4 using Imaris 6.1.5 software (Bitplane) and an Olympus Fluoview 1000 confocal microscope. At this stage MAL13P1.130-GFP (green) is found in a cramp like distribution. Nuclei were stained with DAPI (blue).

  2. 2.

    Supplementary Movie 2

    MAL13P1.130-GFP localization in late schizonts. 360°C rotation of a 3-dimensional representation of a live late schizont stage cell expressing MAL13P1.130-GFP using Imaris 6.1.5 software (Bitplane). It shows the typical ring like staining of MAL13P1.130-GFP (green) as described in Figure 4. Nuclei were stained with DAPI (blue).

  3. 3.

    Supplementary Movie 3

    MAL13P1.130-GFP localization in nascent merozoites. A 360°C rotation of a 3-dimensional representation of a live cell was generated from a late segmented stage parasite as described in Figure 4. At this stage MAL13P1.130-GFP (green) is found distributed in the periphery of nascent merozoites. Nuclei were stained with DAPI (blue).

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DOI

https://doi.org/10.1038/nbt.1597

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