<i>Toxoplasma gondii</i>Genotype Determines MyD88-Dependent Signaling in Infected Macrophages

Kim, Leesun; Butcher, Barbara A.; Lee, Chiang W.; Uematsu, Satoshi; Akira, Shizuo; Denkers, Eric

doi:10.4049/jimmunol.177.4.2584

Cited by 81 publications

(84 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, extracellular tachyzoites of the type I genotype exhibit a potent transmigratory ability that likely facilitates passage across physiological barriers, a trait significantly less prominent in type II and III strains (3). Also, while high intracellular growth rates of type I parasites lead to heavy parasite tissue burdens and Th1-type cytokine overproduction in mice (17,21,36), type II parasites stimulate extensive interleukin-12 production (29,42,44), leading to immunological control of the infection. Thus, while type I parasites seem to rely on virulence traits for efficient parasite dissemination and III) parasites may have refined their ability to utilize host cell migration to ensure efficient dissemination with a low parasitic load, resulting in minimized harm to the host.…”

Section: Discussionmentioning

confidence: 99%

TheToxoplasma gondii-Shuttling Function of Dendritic Cells Is Linked to the Parasite Genotype

et al. 2009

View full text Add to dashboard Cite

Following intestinal invasion, the processes leading to systemic dissemination of the obligate intracellular protozoan Toxoplasma gondii remain poorly understood. Recently, tachyzoites representative of type I, II and III T. gondii populations were shown to differ with respect to their ability to transmigrate across cellular barriers. In this process of active parasite motility, type I strains exhibit a migratory capacity superior to those of the type II and type III strains. Data also suggest that tachyzoites rely on migrating dendritic cells (DC) as shuttling leukocytes to disseminate in tissue, e.g., the brain, where cysts develop. In this study, T. gondii tachyzoites sampled from the three populations were allowed to infect primary human blood DC, murine intestinal DC, or in vitro-derived DC and were compared for different phenotypic traits. All three archetypical lineages of T. gondii induced a hypermigratory phenotype in DC shortly after infection in vitro. Type II (and III) strains induced higher migratory frequency and intensity in DC than type I strains did. Additionally, adoptive transfer of infected DC favored the dissemination of type II and type III parasites over that of type I parasites in syngeneic mice. Type II parasites exhibited stronger intracellular association with both CD11c؉ DC and other leukocytes in vivo than did type I parasites. Altogether, these findings suggest that infected DC contribute to parasite propagation in a strain type-specific manner and that the parasite genotype (type II) most frequently associated with toxoplasmosis in humans efficiently exploits DC migration for parasite dissemination.The obligate intracellular parasite Toxoplasma gondii infects virtually any warm-blooded vertebrate and ϳ25% of the world's human population (27). Most infections generate few or no symptoms. Yet, acute infections are a concern in human medicine, since this opportunistic pathogen causes severe neurological complications in immunocompromised individuals, disseminated congenital infections in the developing fetus, and ocular manifestations in otherwise healthy individuals (27). After ingestion of the parasite, acute infection is characterized by the proliferation of fast-growing stages (tachyzoites) that rapidly disseminate and differentiate into slow-growing stages (bradyzoites) in peripheral tissues, where they may persist for the lifetime of the host (27). In contrast to pathogens that rely on uptake by host cells, T. gondii actively invades host cells, including cells of the immune system, and replicates in a nonfusigenic parasitophorous vacuole (45).Mounting evidence indicates that dendritic cells (DC) play critical roles during T. gondii infection as early sources of protective interleukin-12 responses and mediators of antigen presentation (32,35,37,41). In addition, based on their migratory properties (40) and permissiveness to Toxoplasma infection (6), DC have recently been identified as systemic carriers (Trojan horses) of T. gondii tachyzoites (2,7,30). Yet, the precise roles of ...

show abstract

Section: Discussionmentioning

confidence: 99%

TheToxoplasma gondii-Shuttling Function of Dendritic Cells Is Linked to the Parasite Genotype

et al. 2009

View full text Add to dashboard Cite

show abstract

“…To further investigate the function of this protein, we generated parasites deficient in GRA25. For these experiments, we used type II ME49 parasites, as this strain elicits a more potent immune response and induces higher levels of proinflammatory cytokines, including CCL2, than type I and type III strains (36). Type II is also the better-studied strain in the mouse model, with moderate virulence compared to type I.…”

Section: Qtl Mapping Reveals a Region On Toxoplasma Chromosome IX Thamentioning

confidence: 99%

GRA25 Is a Novel Virulence Factor of Toxoplasma gondii and Influences the Host Immune Response

et al. 2014

View full text Add to dashboard Cite

The obligate intracellular parasite Toxoplasma gondii is able to infect a broad range of hosts and cell types due, in part, to the diverse arsenal of effectors it secretes into the host cell. Here, using genetic crosses between type II and type III Toxoplasma strains and quantitative trait locus (QTL) mapping of the changes they induce in macrophage gene expression, we identify a novel dense granule protein, GRA25. Encoded on chromosome IX, GRA25 is a phosphoprotein that is secreted outside the parasites and is found within the parasitophorous vacuole. In vitro experiments with a type II ⌬gra25 strain showed that macrophages infected with this strain secrete lower levels of CCL2 and CXCL1 than those infected with the wild-type or complemented control parasites. In vivo experiments showed that mice infected with a type II ⌬gra25 strain are able to survive an otherwise lethal dose of Toxoplasma tachyzoites and that complementation of the mutant with an ectopic copy of GRA25 largely rescues this phenotype. Interestingly, the type II and type III versions of GRA25 differ in endogenous expression levels; however, both are able to promote parasite expansion in vivo when expressed in a type II ⌬gra25 strain. These data establish GRA25 as a novel virulence factor and immune modulator.T oxoplasma gondii is an obligate intracellular parasite with the remarkable ability to infect a broad range of mammalian and avian hosts. During infection in the mouse, a natural Toxoplasma host, macrophages are known to play a key role in mounting an immune response to infection via the secretion of cytokines such as interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-␣) (1). The secretion of these cytokines leads to the activation of NK cells and CD4 ϩ and CD8 ϩ T cells (2-4). Although macrophages can themselves be targets of parasite infection, they also can control parasite dissemination through cell-intrinsic, antimicrobial strategies, such as the production of nitric oxide (NO) and reactive oxygen species (ROS) and, in mice, the activation of immunityrelated GTPases (IRGs) (5, 6). Recent studies have shown that inflammatory monocytes, in particular, are recruited to the site of infection by the cytokine CCL2 (monocyte chemotactic protein-1 [MCP-1]) (7, 8). As has been described for infection with several pathogens (9), CCL2 is essential for control of parasite spread and survival of infection in both intraperitoneal (i.p.) and oral Toxoplasma infections (7,8).The strains of Toxoplasma that predominate in Europe and North America, termed types I, II, and III, differ in a wide range of phenotypes, including how they interface with the immune response. The tachyzoite stage of the parasite interacts with the host through secretion of polymorphic proteins from specialized organelles termed rhoptries, which house "ROP" proteins, and dense granules, which contain "GRA" proteins. One such polymorphic protein is the tyrosine kinase ROP16. Upon injection into the host cell, it directly phosphorylates STAT3 and STAT6, and in cells infec...

show abstract

“…Thus, type I strains are highly virulent in mice, whereas types II and III are considerably less virulent and cause less pathology during infection. The stage was set for a major leap in understanding Toxoplasma-host cell interactions by the observation that type II but not type I or type III parasite strains triggered large amounts of macrophage IL-12 and that this was accompanied by strainspecific translocation of NF-B (38,68). By genetic examination of F1 progeny between type II and type III parasite strains, virulence loci were identified, and in this way several secretory rhoptry proteins emerged as important parasite effectors that controlled virulence (6).…”

Section: Rhoptry Protein Rop16 Activates Stat3 and Stat6mentioning

confidence: 99%

An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii

Denkers

Bzik²,

Fox³

et al. 2012

Infect Immun

Self Cite

View full text Add to dashboard Cite

The intracellular protozoan Toxoplasma gondii is well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype.

show abstract

Toxoplasma gondiiGenotype Determines MyD88-Dependent Signaling in Infected Macrophages

Cited by 81 publications

References 59 publications

TheToxoplasma gondii-Shuttling Function of Dendritic Cells Is Linked to the Parasite Genotype

TheToxoplasma gondii-Shuttling Function of Dendritic Cells Is Linked to the Parasite Genotype

GRA25 Is a Novel Virulence Factor of Toxoplasma gondii and Influences the Host Immune Response

An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii

Contact Info

Product

Resources

About