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Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue

Nature volume 445, pages 324–327 (2007)Cite this article

Abstract

Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, can cause severe disease in humans with an immature or suppressed immune system. The outcome of Toxoplasma infection is highly dependent on the strain type, as are many of its in vitro growth properties1. Here we use genetic crosses between type II and III lines to show that strain-specific differences in the modulation of host cell transcription are mediated by a putative protein kinase, ROP16. Upon invasion by the parasite, this polymorphic protein is released from the apical organelles known as rhoptries and injected into the host cell, where it ultimately affects the activation of signal transducer and activator of transcription (STAT) signalling pathways and consequent downstream effects on a key host cytokine, interleukin (IL)-12. Our findings provide a new mechanism for how an intracellular eukaryotic pathogen can interact with its host and reveal important differences in how different Toxoplasma lineages have evolved to exploit this interaction.

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Figure 1: Toxoplasma strain-specific regulation of human gene expression.
Figure 2: Genome-wide scans for association of human gene expression with Toxoplasma genetic markers.
Figure 3: Strain-specific activation of STAT3.
Figure 4: ROP16 is secreted from the parasite and localizes to the host cell nucleus.
Figure 5: ROP16 mediates strain-specific activation of STAT3/6 and consequent downstream effects on IL-12.

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Acknowledgements

This work was supported by grants from the NIH (to J.C.B., J.P.B. and M.W.W.), the Ellison Medical Foundation (to J.C.B.), the USDS (to M.W.W.) and the California Universitywide AIDS Research Program (to J.P.J.S. and S.C.). We thank K. Broman for help with R/qtl and the Stanford Functional Genomics Facility for the human cDNA microarrays used for this study.

Author Contributions J.P.J.S. and S.C. contributed equally to this work. J.P.J.S. performed the microarrays and pathway analyses. S.C. and J.P.J.S. performed the experiments in Fig. 3. S.C. performed the experiments in Fig. 4 and Fig 5. J.P.B., M.E.J. and M.W.W. performed the genetic crosses that produced the progeny D3X1 and JD4. J.P.B. genotyped D3X1 and JD4. J.P.J.S., S.C., J.P.B. and J.C.B. wrote the paper. All authors discussed the results and commented on the manuscript.

The microarray data have been deposited in ArrayExpress with the accession number E-MEXP-783.

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Author notes

  1. J. P. J. Saeij and S. Coller: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Stanford University School of Medicine, Fairchild Building D305, 300 Pasteur Drive, California, 94305-5124, Stanford, USA

    J. P. J. Saeij, S. Coller, J. P. Boyle & J. C. Boothroyd

  2. Department of Veterinary Molecular Biology, College of Agriculture, Montana State University, Montana, 59717, Bozeman, USA

    M. E. Jerome & M. W. White

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  1. J. P. J. Saeij
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  3. J. P. Boyle
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  4. M. E. Jerome
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  6. J. C. Boothroyd
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Correspondence to J. C. Boothroyd.

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Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-6 with legends, Supplementary Methods and additional references. (PDF 1410 kb)

Supplementary Data 1

This file contains Supplementary Data 1 with the array data (Log2 of Cy5/Cy3 normalized ratio (median)) for the genes indicated in Figure 1 (XLS 58 kb)

Supplementary Data 2

This file contains Supplementary Data 2 with the raw array data (Log2 of Cy5/Cy3 normalized ratio (median)) for all cDNAs. For the cDNAs that mapped significantly to a Toxoplasma genetic marker the LOD-score value at each genetic marker is indicated. (XLS 26202 kb)

Supplementary Data 3

This file contains Supplementary Data 3 with the array data for comparing HFFs infected with type II vs. type II:ROP16I strains. (XLS 24327 kb)

Supplementary legends

This file contains legends for Supplementary Data 1-3 (DOC 24 kb)

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Saeij, J., Coller, S., Boyle, J. et al. Toxoplasma co-opts host gene expression by injection of a polymorphic kinase homologue. Nature 445, 324–327 (2007). https://doi.org/10.1038/nature05395

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