Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent...

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Published in	Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 23; pp. 9625 - 9630
Main Authors	Reese, Michael L, Zeiner, Gusti M, Saeij, Jeroen P.J, Boothroyd, John C, Boyle, Jon P
Format	Journal Article
Language	English
Published	United States National Academy of Sciences 07.06.2011 National Acad Sciences
Subjects	Adaptations Alleles Amino Acid Sequence Animals Apicomplexa Bacterial infections Biological Sciences Cells, Cultured copy number Enzymes Evolution Female genes Genetic Complementation Test Genetic loci Genetic Loci - genetics Genetic Variation Genomes Genomics Host range Hot spots Humans Infection Infections loci Male Mice Mice, Inbred BALB C Molecular Sequence Data Multigene Family - genetics Mutation Parasite hosts Parasites Phenotypes Phylogeny Polymorphism, Genetic Positive selection Protein isoforms Protein Isoforms - genetics proteins Protozoan Proteins - classification Protozoan Proteins - genetics Quantitative trait loci Sampling Sequence Homology, Amino Acid Species Specificity Toxoplasma - classification Toxoplasma - genetics Toxoplasma - pathogenicity Toxoplasma gondii toxoplasmosis Toxoplasmosis, Animal - parasitology Virology Virulence Virulence - genetics virulent strains
Online Access	Get full text
ISSN	0027-8424 1091-6490 1091-6490
DOI	10.1073/pnas.1015980108

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Abstract	Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4-10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence.
AbstractList	Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4-10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence. Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4-10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence.Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4-10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence. Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4 - 10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence. [PUBLICATION ABSTRACT] Toxoplasma gondii , an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4–10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been ( i ) catalytically inactivated, ( ii ) expanded in number, and ( iii ) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma ’s successful adaptation to a wide host range and has resulted in dramatic differences in virulence.
Author	Saeij, Jeroen P.J Reese, Michael L Zeiner, Gusti M Boothroyd, John C Boyle, Jon P
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BackLink	https://www.ncbi.nlm.nih.gov/pubmed/21436047$$D View this record in MEDLINE/PubMed
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Notes	http://dx.doi.org/10.1073/pnas.1015980108 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 Edited by Thomas E. Wellems, National Institutes of Health, Bethesda, MD, and approved February 25, 2011 (received for review October 26, 2010) 2Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139. Author contributions: M.L.R., G.M.Z., J.C.B., and J.P.B. designed research; M.L.R., G.M.Z., J.P.S., J.C.B., and J.P.B. performed research; M.L.R., G.M.Z., J.P.S., and J.P.B. analyzed data; and M.L.R., J.C.B., and J.P.B. wrote the paper. 1Present address: Molecular Tools Lab, Agilent Technologies, Santa Clara, CA 95051. 3J.C.B. and J.P.B. contributed equally to this work.
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Snippet	Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an... Toxoplasma gondii , an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an... Toxoplasma gondii , an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an...
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SubjectTerms	Adaptations Alleles Amino Acid Sequence Animals Apicomplexa Bacterial infections Biological Sciences Cells, Cultured copy number Enzymes Evolution Female genes Genetic Complementation Test Genetic loci Genetic Loci - genetics Genetic Variation Genomes Genomics Host range Hot spots Humans Infection Infections loci Male Mice Mice, Inbred BALB C Molecular Sequence Data Multigene Family - genetics Mutation Parasite hosts Parasites Phenotypes Phylogeny Polymorphism, Genetic Positive selection Protein isoforms Protein Isoforms - genetics proteins Protozoan Proteins - classification Protozoan Proteins - genetics Quantitative trait loci Sampling Sequence Homology, Amino Acid Species Specificity Toxoplasma - classification Toxoplasma - genetics Toxoplasma - pathogenicity Toxoplasma gondii toxoplasmosis Toxoplasmosis, Animal - parasitology Virology Virulence Virulence - genetics virulent strains
Title	Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence
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