EC Accepts, published online ahead of print on 22 May 2009

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Eukaryotic Cell doi:10.1128/EC.00107-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Forward genetics in Toxoplasma gondii reveals a family of rhoptry kinases that mediates pathogenesis

L. David Sibley^*, Wei Qiu, Sarah Fentress, Sonya J. Taylor, Asis Khan, and Raymond Hui

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis,. MO 63130; Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada

^* To whom correspondence should be addressed. Email: sibley{at}borcim.wustl.edu.

Toxoplasma gondii is a widespread protozoan parasite that is both an important opportunistic pathogen and a model for related parasites in the phylum Apicomplexa. Toxoplasma offers a number of experimental advantages including convenient in vitro culture, small animal models, and forward and reverse genetic systems. Here we describe the development of forward genetic strategies to identify parasite genes that contribute to pathogenesis in laboratory mice. These studies led to the unexpected finding that a family of secretory serine/threonine kinases controls acute virulence in the mouse model. These S/T kinases are injected from secretory organelles in the parasite called the rhoptries, into the host cell during invasion. The rhoptry (ROP) protein family includes both pseudokinases and catalytically active kinases. Active ROPs are highly polymorphic, show dramatic differences in expression levels between strains, and are under strong selective pressure. Recent structural analysis indicates they also differ substantially from well-characterized kinases in animal cells. ROP kinases alter host cell gene transcription and set up an environment that favors parasite survival and replication, thus enhancing pathogenicity. The powerful combination of forward genetic screens and reverse genetic testing available in T. gondii will allow further characterization of these important virulence factors.