Rhoptries: an arsenal of secreted virulence factors

Bradley, Peter J.; Sibley, L. David

doi:10.1016/j.mib.2007.09.013

Cited by 178 publications

(151 citation statements)

References 33 publications

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“…Sexual crosses between members of these lineages (Type I × Type III and Type II × Type III) (6, 7) have shown that virulence in mice segregates among F1 progeny (8). This has allowed for the discovery of a number of virulence loci using quantitative trait loci (QTL) mapping (9, 10).Toxoplasma secretes an arsenal of effector proteins into its host cell from specialized secretory organelles termed rhoptries and dense granules (11)(12)(13)(14). Given the selective pressure of the interaction with its varied hosts, it is not surprising that many of Toxoplasma's effectors are among the most polymorphic proteins between the major strains.…”

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confidence: 99%

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Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Reese

Zeiner

Boothroyd

et al. 2011

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

239

303

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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.copy number variation | host-pathogen interaction T he evolutionary pressure on the molecules that form the interface between a pathogenic organism and its host has been likened to an arms race (1, 2) and has been proposed to give rise to highly polymorphic genes such as those that encode host MHC and viral capsid proteins. Whereas most pathogens have a single or restricted range of hosts with which they coevolve, the obligate intracellular parasite Toxoplasma gondii can infect virtually any cell of almost any warm-blooded animal, a remarkable feat from an evolutionary perspective.Different strains of Toxoplasma cause significantly different disease in mice (3) and humans as well (4, 5). In North America and Europe, three strains have grown to dominate Toxoplasma's genetic landscape, and they are characterized by distinct disease outcomes in mice: although a single Type I parasite is uniformly lethal to a mouse, Type II and III parasites have a lethal dose (LD 50 ) ranging from 10 2 to 10 5 (3). Sexual crosses between members of these lineages (Type I × Type III and Type II × Type III) (6, 7) have shown that virulence in mice segregates among F1 progeny (8). This has allowed for the discovery of a number of virulence loci using quantitative trait loci (QTL) mapping (9, 10).Toxoplasma secretes an arsenal of effector proteins into its host cell from specialized secretory organelles termed rhoptries and dense granules (11)(12)(13)(14). Given the selective pressure...

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mentioning

confidence: 99%

“…Toxoplasma secretes an arsenal of effector proteins into its host cell from specialized secretory organelles termed rhoptries and dense granules (11)(12)(13)(14). Given the selective pressure of the interaction with its varied hosts, it is not surprising that many of Toxoplasma's effectors are among the most polymorphic proteins between the major strains.…”

mentioning

confidence: 99%

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Reese

Zeiner

Boothroyd

et al. 2011

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

239

303

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“…5 Many studies have examined the function of ROPs, but few have studies the function of GRAs. 6 In this study, we investigate variation in the expression of GRA1 and in the rate of cell apoptosis during T. gondii invasion into HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

Increased Expression of Toxoplasma Gondii GRA1 Suppresses Host Cell Apoptosis

Chen¹

2017

JBMOA

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Suppression of host cell apoptosis enable Toxoplasma gondii to proliferate, but the mechanism is not well understood. We explore the relationship between the expression of T. gondii dense granule protein 1 (GRA1) and host HeLa cell apoptosis. We inserted the T. gondii gra1 coding gene into a pET32a vector and produced recombinant GRA1 (rGRA1) in E. coli Rosetta strain. We then immunized rabbits with rGRA1 to produce anti-GRA1 serum and infected HeLa cells with T. gondii tachyzoites. We determined the expression of T. gondii GRA1 by Western blotting with anti-GRA1 serum and determined apoptosis of HeLa cells via the Annexin V-FITC/PI method. All the experiments were repeated for three times in the same condition. The expression of GRA1 decreased gradually after T. gondii infection. The rate of HeLa cell apoptosis increased more rapidly in the infected cells than in the uninfected cells. Our results suggest that the suppression of host cell apoptosis is related to the expression of T. gondii GRA1 expression.

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“…Most of them are Rhoptry bulb proteins (i.e. ROP16, ROP18 and ROP5) and they are secreted into host cell cytoplasm, often at the onset of cell invasion before complete internalization, and further subvert host cellular functions (Bradley and Sibley, 2007). Aside from these Rhoptry proteins, a member of the dense granule (DG) protein family, GRA15 was shown to positively activate NF-kB (p65/RelA subunit) and IL-12 production (Melo et al, 2011;Rosowski et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Toxoplasmaexports dense granule proteins beyond the vacuole to the host cell nucleus and rewires the host genome expression

2014

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SummaryToxoplasma gondii is the most widespread apicomplexan parasite and occupies a large spectrum of niches by infecting virtually any warmblooded animals. As an obligate intracellular parasite, Toxoplasma has evolved a repertoire of strategies to fine-tune the cellular environment in an optimal way to promote growth and persistence in host tissues hence increasing the chance to be transmitted to new hosts. Short and long-term intracellular survival is associated with Toxoplasma ability to both evade the host deleterious immune defences and to stimulate a beneficial immune balance by governing host cell gene expression. It is only recently that parasite proteins responsible for driving these transcriptional changes have been identified. While proteins contained in the apical secretory Rhoptry organelle have already been identified as bona fide secreted effectors that divert host signalling pathways, recent findings revealed that dense granule proteins should be added to the growing list of effectors as they reach the host cell cytoplasm and nucleus and target various host cell pathways in the course of cell infection. Herein, we emphasize on a novel subfamily of dense granule resident proteins, exemplified with the GRA16 and GRA24 members we recently discovered as both are exported beyond the vacuole-containing parasites and reach the host cell nucleus to reshape the host genome expression.

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Rhoptries: an arsenal of secreted virulence factors

Cited by 178 publications

References 33 publications

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Increased Expression of Toxoplasma Gondii GRA1 Suppresses Host Cell Apoptosis

Toxoplasmaexports dense granule proteins beyond the vacuole to the host cell nucleus and rewires the host genome expression

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