Strain-specific activation of the NF-κB pathway by GRA15, a novel <i>Toxoplasma gondii</i> dense granule protein

Rosowski, Emily E.; Lu, Diana; Julien, Lindsay; Rodda, Lauren B.; Gaiser, Rogier; Jensen, Kirk D. C.; Saeij, Jeroen P. J.

doi:10.1084/jem.20100717

Cited by 367 publications

(598 citation statements)

References 58 publications

(104 reference statements)

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“…Our results presented here showed that ROP18 phosphorylates p65 at Ser-468 to promote its ubiquitin-dependent degradation; thus, the nuclear localization of p65 cannot be obviously observed in cells infected with type I strains, consistent with previous studies (9,12,13,19,20). Our data demonstrated that infection with T. gondii type I results in p65 ubiquitin-dependent degradation, which blocks the nuclear translocation of p65 and induces the consequent termination of the NF-B pathway.…”

supporting

confidence: 91%

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Toxoplasma gondii Virulence Factor ROP18 Inhibits the Host NF-κB Pathway by Promoting p65 Degradation

Chen

et al. 2014

Journal of Biological Chemistry

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Background: ROP18 is a Toxoplasma secreted Ser/Thr protein kinase important for acute virulence. Results: ROP18 phosphorylates host p65 at Ser-468 and target this protein to the ubiquitin-dependent degradation. Conclusion: ROP18 inhibits the host NF-B pathway by promoting p65 degradation. Significance: These findings reveal a novel molecular mechanism by which type I strain manipulates the host immune system to facilitate infection.

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confidence: 91%

“…There have been several controversial studies claiming both the inhibition and activation of host NF-B pathway by T. gondii (9). Some studies have shown that type I strains inhibit NF-B pathway and the recruitment and activation of immune cells, resulting in the enhanced survival of the parasites (10 -14).…”

mentioning

confidence: 99%

Toxoplasma gondii Virulence Factor ROP18 Inhibits the Host NF-κB Pathway by Promoting p65 Degradation

Chen

et al. 2014

Journal of Biological Chemistry

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“…A concept that is now gaining acceptance is that induction of proinflammatory cytokines essential for in vivo control of acute Toxoplasma infection involves intracellular signaling from endosomal and cytoplasmic pattern recognition receptors (PRRs) (22)(23)(24)(25)(26). Interestingly, the inflammatory cytokines IL-12 and IL-1β are both induced differentially by avirulent, but not virulent, Toxoplasma strains (9,27,28), presumably through intracellular activation of TLRs and other PRRs. However, how these intracellular PRRs are activated during live Toxoplasma infection is still poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Avirulent strains of Toxoplasma gondii infect macrophages by active invasion from the phagosome

Zhao

Marple

Ferguson

et al. 2014

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

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Unlike most intracellular pathogens that gain access into host cells through endocytic pathways, Toxoplasma gondii initiates infection at the cell surface by active penetration through a moving junction and subsequent formation of a parasitophorous vacuole. Here, we describe a noncanonical pathway for T. gondii infection of macrophages, in which parasites are initially internalized through phagocytosis, and then actively invade from within a phagosomal compartment to form a parasitophorous vacuole. This phagosome to vacuole invasion (PTVI) pathway may represent an intermediary link between the endocytic and the penetrative routes for host cell entry by intracellular pathogens. The PTVI pathway is preferentially used by avirulent strains of T. gondii and confers an infectious advantage over virulent strains for macrophage tropism.virulence | Trojan horse | apicomplexa | phagocytes P hagocytosis is one of the most ancient defense mechanisms for the host to destroy invasive pathogens. However, most intracellular pathogens exploit this very pathway for internalization and survival in phagocytes (1). A notable exception to this paradigm is the infection pathway used by apicomplexan parasites-exemplified by Toxoplasma gondii. The current consensus model of T. gondii infection suggests that the parasite actively invades host cells by forming a moving junction (MJ) at the host cell surface (2). Penetration of T. gondii through this junction is largely driven by its own actin motor complex (3). The parasitophorous vacuoles formed by this pathway are nonfusogenic with the host endocytic system, thus evading lysosome-mediated destruction (4-6). However, recent reports including the findings that host F-actin participates in entry by T. gondii (7), and that the parasite is still able to infect cells, albeit much less efficiently, even without some key components of the invasion machinery (8), suggest the existence of alternative infection pathways for Toxoplasma. The active penetration model was defined largely by using nonphagocytic host cells and hypervirulent strains of the parasite. Unlike their virulent counterparts, the interaction of avirulent Toxoplasma strains with macrophage and dendritic cell results in heightened innate cytokine and chemokine production (9) and the development of a "hypermotile" host cellular phenotype (10), which promotes the control of acute infection and mediates dissemination into sites of parasite latency (11,12). Here, we investigated whether avirulent parasites interact with phagocytic host cells in a fundamentally different way from the outset. We found that the avirulent Toxoplasma strains infect macrophages initially via phagocytosis and subsequent active penetration from within the phagosome to form a parasitophorous vacuole. This hybrid invasion pathway may represent an intermediary link between the endocytic and the penetrative routes for host cell entry by intracellular pathogens. ResultsTo investigate whether avirulent Toxoplasma (PTG, type II strain) uses the active penetration p...

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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.…”

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.

234

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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Strain-specific activation of the NF-κB pathway by GRA15, a novel Toxoplasma gondii dense granule protein

Abstract: The Toxoplasma gondii granule protein GRA15 activates the NF-κB pathway.

Cited by 367 publications

References 58 publications

Toxoplasma gondii Virulence Factor ROP18 Inhibits the Host NF-κB Pathway by Promoting p65 Degradation

Toxoplasma gondii Virulence Factor ROP18 Inhibits the Host NF-κB Pathway by Promoting p65 Degradation

Avirulent strains of Toxoplasma gondii infect macrophages by active invasion from the phagosome

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

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