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Title:   Author  item
                                            BEHNKE, M - Washington University School Of Medicineitem
                                            KAHN, A - Washington University School Of Medicineitem
                                            WOOTTON, J - National Institutes Of Health (NIH)item
                                            Dubey, Jitenderitem
                                            TANG, K - Washington University School Of Medicineitem
                                            SIBLEY, L - Washington University School Of Medicine
  Submitted to: Proceedings of the National Academy of Sciences (PNAS)
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 2/1/2011
                                    Publication  Date: 9/15/2011
                                    Citation: Behnke, M., Kahn, A., Wootton, J., Dubey, J.P., Tang, K., Sibley, L.D. 2011. Virulence differences in Toxoplasma mediated by amplification of a family of polymorphic pseudokinases. Proceedings of the National Academy of Sciences. 108:9631-9636.Interpretive Summary: Toxoplasma gondii is a single-celled parasite of all warm-blooded hosts worldwide. It causes mental retardation and loss of vision in children, and abortion in livestock. Cats are the main reservoir of T. gondii because they are the only hosts that can excrete the resistant stage (oocyst) of the parasite in the feces. Humans become infected by eating undercooked meat from infected animals and food and water contaminated with oocysts. Why some people become sick whereas others do not is not clear. In the present study scientists document that one gene can control virulence of Toxoplasma in the mouse model. The results will be of interest to biologists, parasitologists, and public health workers.
                                Technical Abstract: The population structure of Toxoplasma gondii includes three highly prevalent clonal lineages, types I, II, and III, which differ greatly in virulence in the mouse model.  Previous studies have implicated a family of serine threonine protein kinases found in rhoptries (ROPs) as important in mediating virulence differences between types I vs. III and II vs. III.  Here, we explored the genetic basis of differences in virulence between the highly virulent type I lineage and moderately virulent type II based on a new genetic cross and linkage mapping.  Genome-wide association revealed a single quantitative trait locus controls the > 4 log difference in lethality between these strains.  Neither ROP16 nor ROP18, previously implicated in virulence differences in T. gondii, were found to contribute to differences between types I and II.  Instead, the major virulence locus contained a cluster of pseudokinases denoted as rhoptry protein 5 (ROP5); this locus contains a tandem cluster of polymorphic alleles that differed in expression levels between strains.  ROP5 alleles contained only part of the catalytic triad of canonical S/T kinases, and consistent with this they lack demonstrable kinase activity in vitro.  Genetic disruption of the rop5 locus in the type I lineage lead to a > 4 log increase in the lethal dose, and surviving mice developed lasting immunity and were protected from an otherwise lethal challenge.  These findings reveal that amplification of a polymorphic cluster of pseudokinases plays an important role in pathogenesis of toxoplasmosis in the mouse model.


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