Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes

Lorenzi, Hernán; Khan, Asis; Behnke, Michael S.; Namasivayam, Sivaranjani; Swapna, Lakshmipuram S.; Hadjithomas, Michalis; Karamycheva, Svetlana; Pinney, Deborah F.; Brunk, Brian P.; Ajioka, James W.; Ajzenberg, Daniel; Boothroyd, John C.; Boyle, Jon P.; Dardé, Marie Laure; Diaz‐Miranda, Maria Alejandra; Dubey, J. P.; Fritz, Heather M.; Gennari, Solange Maria; Gregory, Brian D.; Kim, Kami; Saeij, Jeroen P. J.; Su, Chunlei; White, Michael; Zhu, Xing‐Quan; Howe, Daniel K.; Rosenthal, Benjamin M.; Grigg, Michael E.; Parkinson, John; Liu, Liang; Kissinger, Jessica C.; Roos, David S.; Sibley, L. David

doi:10.1038/ncomms10147

Cited by 232 publications

(338 citation statements)

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“…Phylogenetic network of major T. gondii strain types based on genome-wide single nucleotide polymorphisms (72). The major strain types are denoted by reference strains (haplotypes in parentheses) that are clustered by clades.…”

Section: Figurementioning

confidence: 99%

“…Sampling from Africa is somewhat sporadic, but at least one haplotype commonly found in Africa (i.e., type 14) is related to type 6 strains found in both Europe and South America, suggesting a global distribution for this clade (78). Recent studies based on whole-genome sequencing of more than 60 strains of T. gondii revealed that the population structure is shaped by recent admixture resulting in coinheritance of large chromosomal haploblocks that are conserved between members of a common clade (72). Moreover, these conserved haploblocks are enriched in secreted pathogenicity determinants that interact with the host (72), as discussed further below.…”

Section: Figurementioning

confidence: 99%

“…Both ROP18 and ROP5 genes are highly polymorphic, and ROP5 is an example of a gene that shows copy number variation (CNV), ranging from 2 to more than 10 copies per genome in different strains, indicating evidence of positive selection (9,98). Such polymorphic and/or tandemly repeated genes are often coinherited in large haploblocks that are conserved among members of different clades, suggesting they provide a selective advantage (72).…”

Section: Copy Number Variation (Cnv)mentioning

confidence: 99%

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Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Behnke

Dubey

Sibley

2016

Annu. Rev. Microbiol.

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Toxoplasma gondii is a widespread parasite of warm-blooded vertebrates that also causes opportunistic infections in humans. Rodents are a natural host for asexually replicating forms, whereas cats serve as the definitive host for sexual development. The laboratory mouse provides a model to study pathogenesis. Strains of T. gondii are globally diverse, with more than 16 distinct haplogroups clustered into 6 major clades. Forward genetic analysis of genetic crosses between different lineages has been used to define the molecular basis of acute virulence in the mouse. These studies have identified a family of secretory serine/threonine rhoptry kinases that target innate immune pathways to protect intracellular parasites from destruction. Rhoptry kinases target immunity-related GTPases, a family of immune effectors that is expanded in rodents. Similar forward genetic studies may be useful to define the basis of pathogenesis in other hosts, including humans, where infections of different strains present with variable clinical severity.

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Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Copy Number Variation (Cnv)mentioning

confidence: 99%

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Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Behnke

Dubey

Sibley

2016

Annu. Rev. Microbiol.

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“…gondii has a complex life cycle, and the parasite's ability to differentiate through its life stages in response to stresses and environmental conditions is fundamental for its pathogenicity and transmission (3). Transcriptome analyses have revealed that a large percentage of mRNAs show life stage-specific expression (4) and/or cell cycle regulation (5).…”

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confidence: 99%

O -fucosylated glycoproteins form assemblies in close proximity to the nuclear pore complexes of Toxoplasma gondii

Bandini

Haserick

Motari

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Toxoplasma gondii is an intracellular parasite that causes disseminated infections in fetuses and immunocompromised individuals. Although gene regulation is important for parasite differentiation and pathogenesis, little is known about protein organization in the nucleus. Here we show that the fucose-binding Aleuria aurantia lectin (AAL) binds to numerous punctate structures in the nuclei of tachyzoites, bradyzoites, and sporozoites but not oocysts. AAL also binds to Hammondia and Neospora nuclei but not to more distantly related apicomplexans. Analyses of the AAL-enriched fraction indicate that AAL binds O-linked fucose added to Ser/Thr residues present in or adjacent to Ser-rich domains (SRDs). Sixty-nine Ser-rich proteins were reproducibly enriched with AAL, including nucleoporins, mRNA-processing enzymes, and cell-signaling proteins. Two endogenous SRDs-containing proteins and an SRD-YFP fusion localize with AAL to the nuclear membrane. Superresolution microscopy showed that the majority of the AAL signal localizes in proximity to nuclear pore complexes. Host cells modify secreted proteins with O-fucose; here we describe the O-fucosylation pathway in the nucleocytosol of a eukaryote. Furthermore, these results suggest O-fucosylation is a mechanism by which proteins involved in gene expression accumulate near the NPC.toxoplasma | fucose | nuclear glycosylation | nuclear pore complex T he apicomplexan parasite Toxoplasma gondii causes disseminated infections in humans, and these infections can lead to severe damage in immunocompromised individuals and fetuses (1, 2). There is no human vaccine against T. gondii, and recently the price of pyrimethamine, the drug used to treat toxoplasmosis in the United States, has increased more than 50-fold (2).T. gondii has a complex life cycle, and the parasite's ability to differentiate through its life stages in response to stresses and environmental conditions is fundamental for its pathogenicity and transmission (3). Transcriptome analyses have revealed that a large percentage of mRNAs show life stage-specific expression (4) and/or cell cycle regulation (5). Recent studies have increased our understanding of gene expression in T. gondii by identifying the AP2 family of transcription factors (6-8) and by describing posttranslational modifications (PTMs) of histones and some of the enzymes responsible for them (9-11). However, little is known about protein organization at the nuclear periphery, a subnuclear compartment that plays a critical role in transcriptional regulation in many eukaryotes. In particular, the gene-gating model (12) suggests that the nuclear pore complex (NPC) has a role in transcriptional regulation and chromatin organization as well as in protein and mRNA transport (13,14).In T. gondii chromodomain protein 1 localizes with heterochromatin at the nuclear periphery (15), and centromeres sequester to an apical nuclear region (16). Although the nuclear localization signal (NLS) and importin-α system are present, key nuclear import and export molecules are...

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“…ponents in order to create an environment in which they can survive (64)(65)(66)(67)(68). Without this ability, the host cell's innate defense mechanisms could overcome the parasite and prevent its reproduction or egress (69).…”

Section: Compounds With Proposed Modes Of Actionmentioning

confidence: 99%

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

McFarland

Zach

Wang

et al. 2016

Antimicrob Agents Chemother

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Toxoplasma gondii is a ubiquitous apicomplexan parasite capable of infecting humans and other animals. Current treatment options for T. gondii infection are limited and most have drawbacks, including high toxicity and low tolerability. Additionally, no FDA-approved treatments are available for pregnant women, a high-risk population due to transplacental infection. Therefore, the development of novel treatment options is needed. To aid this effort, this review highlights experimental compounds that, at a minimum, demonstrate inhibition of in vitro growth of T. gondii. When available, host cell toxicity and in vivo data are also discussed. The purpose of this review is to facilitate additional development of anti-Toxoplasma compounds and potentially to extend our knowledge of the parasite.

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Local admixture of amplified and diversified secreted pathogenesis determinants shapes mosaic Toxoplasma gondii genomes

Cited by 232 publications

References 67 publications

Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

Genetic Mapping of Pathogenesis Determinants inToxoplasma gondii

O -fucosylated glycoproteins form assemblies in close proximity to the nuclear pore complexes of Toxoplasma gondii

Review of Experimental Compounds Demonstrating Anti-Toxoplasma Activity

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