Reports

A Secreted Serine-Threonine Kinase Determines Virulence in the Eukaryotic Pathogen Toxoplasma gondii

S. Taylor,^1* A. Barragan,^1,2* C. Su,^1,3* B. Fux,¹ S. J. Fentress,¹ K. Tang,¹ W. L. Beatty,¹ H. El Hajj,⁴ M. Jerome,⁵ M. S. Behnke,⁵ M. White,⁵ J. C. Wootton,⁶ L. D. Sibley¹

Toxoplasma gondii strains differ dramatically in virulence despite being genetically very similar. Genetic mapping revealed two closely adjacent quantitative trait loci on parasite chromosome VIIa that control the extreme virulence of the type I lineage. Positional cloning identified the candidate virulence gene ROP18, a highly polymorphic serine-threonine kinase that was secreted into the host cell during parasite invasion. Transfection of the virulent ROP18 allele into a nonpathogenic type III strain increased growth and enhanced mortality by 4 to 5 logs. These attributes of ROP18 required kinase activity, which revealed that secretion of effectors is a major component of parasite virulence.

¹ Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63130, USA.
² Swedish Institute for Infectious Disease Control and Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, 141 86 Stockholm, Sweden.
³ Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA.
⁴ Unité Mixte de Recherche (Joint Research Unit) CNRS 5539, University Montpellier 2, Place Eugene Bataillon, 34095 Montpellier Cedex 5, France.
⁵ Department of Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA.
⁶ Computational Biology Branch, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20894, USA.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: sibley{at}borcim.wustl.edu

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Organellar dynamics during the cell cycle of Toxoplasma gondii.

M. Nishi, K. Hu, J. M. Murray, and D. S. Roos (2008)
J. Cell Sci. 121, 1559-1568
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Phosphoinositide-3-Kinase-Dependent, MyD88-Independent Induction of CC-Type Chemokines Characterizes the Macrophage Response to Toxoplasma gondii Strains with High Virulence.

C. W. Lee, W. Sukhumavasi, and E. Y. Denkers (2007)
Infect. Immun. 75, 5788-5797
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Presentation of Toxoplasma gondii Antigens via the Endogenous Major Histocompatibility Complex Class I Pathway in Nonprofessional and Professional Antigen-Presenting Cells.

F. Dzierszinski, M. Pepper, J. S. Stumhofer, D. F. LaRosa, E. H. Wilson, L. A. Turka, S. K. Halonen, C. A. Hunter, and D. S. Roos (2007)
Infect. Immun. 75, 5200-5209
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Recent transcontinental sweep of Toxoplasma gondii driven by a single monomorphic chromosome.

A. Khan, B. Fux, C. Su, J. P. Dubey, M. L. Darde, J. W. Ajioka, B. M. Rosenthal, and L. D. Sibley (2007)
PNAS 104, 14872-14877
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Discovery of parasite virulence genes reveals a unique regulator of chromosome condensation 1 ortholog critical for efficient nuclear trafficking.

M. B. Frankel, D. G. Mordue, and L. J. Knoll (2007)
PNAS 104, 10181-10186
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Polymorphic Secreted Kinases Are Key Virulence Factors in Toxoplasmosis.

J. P. J. Saeij, J. P. Boyle, S. Coller, S. Taylor, L. D. Sibley, E. T. Brooke-Powell, J. W. Ajioka, and J. C. Boothroyd (2006)
Science 314, 1780-1783
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