The Toxoplasma surface protein SAG1 triggers efficient in vitro secretion of chemokine ligand 2 (CCL2) from human fibroblasts

Brenier-Pinchart, Marie-Pierre; Villena, Isabelle; Mercier, Corinne; Durand, François; Simon, Josiane; Cesbron-Delauw, Marie-France; Pelloux, Hervé

doi:10.1016/j.micinf.2005.06.023

Cited by 16 publications

(9 citation statements)

References 33 publications

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“…Although the growth of the SAG1 mutant is very slow, the fact that the SAG1 mutant is still able to infect host cells in the presence of heparin support the hypothesis for additional cell surface GAG-binding proteins (Lekutis et al 2001;Brenier-Pinchart et al 2006) but also for non-GAG-binding pathways. Together, these data suggest that cell surface GAGs are involved in the early steps of attachment and the invasion of Vero cells by T. gondii tachyzoites and furthermore that the sulfate groups of GAGs are critical for the binding interactions.…”

Section: Gra2 Deletion Mutant (mentioning

confidence: 66%

“…For Apicomplexa, a prerequisite for invasion is the attachment of the parasite to the host cell, as well as reorientation prior to entering the host, steps that are mediated by both parasite and host cell surface molecules (Mineo et al 1993;Jacquet et al 2001). Considering that T. gondii can infect a wide variety of nucleated cells and that T. gondii mutants deficient in surface proteins such as SAG1 can still infect host cells (Lekutis et al 2001;Brenier-Pinchart et al 2006), parasites must be able to access multiple adhesion molecules and overlapping pathways to invade cells (Soldati et al 2004). However, because these parasites can utilize multiple redundant invasion pathways, it has been difficult to assess the relative contribution of individual binding events to the infection process.…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasma gondii secretory proteins bind to sulfated heparin structures

Azzouz¹,

Kamena²,

Laurino³

et al. 2012

Glycobiology

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Toxoplasma gondii is the causative agent of toxoplasmosis, one of the most widespread infections in humans and animals, and is a major opportunistic pathogen in immunocompromised patients. Toxoplasma gondii is unique as it can invade virtually any nucleated cell, although the mechanisms are not completely understood. Parasite attachment to the host cell is a prerequisite for reorientation and penetration and likely requires the recognition of molecules at the host cell surface. It has been reported that the affinity of tachyzoites, the invasive form of T. gondii, for host cells can be inhibited by a variety of soluble-sulfated glycosaminoglycans (GAGs), such as heparan sulfate. Using heparin-functionalized zeolites in the absence of host cells, we visualized heparin-binding sites on the surface of tachyzoites by confocal and atomic force microscopy. Furthermore, we report that protein components of the parasite rhoptry, dense granule and surface bind GAGs. In particular, the proteins ROP2 and ROP4 from the rhoptry, GRA2 from the dense granules and the surface protein SAG1 were found to bind heparin. The binding specificities and affinities of individual parasite proteins for natural heparin and heparin oligosaccharides were determined by a combination of heparin oligosaccharide microarrays and surface plasmon resonance. Our results suggest that interactions between sulfated GAGs and parasite surface antigens contribute to T. gondii attachment to host cell surfaces as well as initiating the invasion process, while rhoptries and dense granule organelles may play an important role during the establishment of the infection and during the life of the parasite inside the parasitophorous vacuole.

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Section: Gra2 Deletion Mutant (mentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii secretory proteins bind to sulfated heparin structures

Azzouz¹,

Kamena²,

Laurino³

et al. 2012

Glycobiology

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“…[1][2][3][4][5] In the oral Toxoplasma gondii infection, enterocytes can initiate innate immunological events that lead to a robust inflammatory process in the gut. 3 Tissue samples isolated from the small intestine of T. gondii infected mice display a significant increase in chemokine secretion including monocyte chemotactic protein 1 (CCL2) and interferon (IFN)-␥ inducible protein (CXCL10), and to a lesser extent, both macrophage inflammatory proteins 1␣ and ␤ (CCL3 and CCL4), as well as CXCL2 regulated on activation and normally T-cell-expressed (CCL5).…”

mentioning

confidence: 99%

CCR2 Receptor Is Essential to Activate Microbicidal Mechanisms to Control Toxoplasma gondii Infection in the Central Nervous System

Benevides

Milanezi

Yamauchi

et al. 2008

The American Journal of Pathology

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Chemokines comprise a structurally related family of cytokines that regulate leukocyte trafficking. Because infection with Toxoplasma gondii can induce an important inflammatory reaction that, if left uncontrolled, can lead to death, we investigated the role of the chemokine receptor CCR2 in T. gondii infection. We orally infected CCR2 ؊/؊ mice with five ME-49 T. gondii cysts and monitored morbidity, survival, and immune response thereafter. The CCR2 ؊/؊ mice displayed higher susceptibility to infection as all mice died on day 28 after infection. Despite similar Th1 responses, a more evident anti-inflammatory response was induced in the peripheral organs of CCR2 ؊/؊ mice compared with wild-type C57BL/6 mice. Additionally, CCR2؊/؊ mice presented greater parasitism and a milder inflammatory reaction in their peripheral organs with lesser CD4 ؉ and MAC-1 ؉ and greater CD8 ؉ cell migration. The parasite load decreased in these organs in CCR2 ؊/؊ mice but remained uncontrolled in the central nervous system. Additionally, we observed down-regulated inducible nitric oxide synthase expression in peripheral organs from CCR2 ؊/؊ mice that was associated with a small nitric oxide production by spleen macrophages. In conclusion, in the absence of CCR2, another mechanism is activated to control tissue parasitism in peripheral organs. Nevertheless, CCR2 is essential for the activation of microbicidal mediators that control T. gondii replication in the central nervous system.

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“…SAG1 knockout and complemented SAG1 knockout parasites were created by Michael Grigg in the laboratory of John Boothroyd (Stanford University) and supplied by Ira Blader (University of Oklahoma) (1,22). Anti-Toxoplasma antibody was supplied by Andrew Hemphill (University of Bern, Bern, Switzerland).…”

Section: Methodsmentioning

confidence: 99%

“…To test this hypothesis, we monitored the effects of Laz on a mutant Toxoplasma clone lacking SAG1 (SAG1KO) relative to a complemented version of SAG1KO, engineered to stably express ectopic SAG1 (1,22). Figure 6 shows that the growth inhibition caused by Laz is diminished in parasites lacking the SAG1 protein.…”

Section: Effects Of Azurin and Laz On Toxoplasma In Vitromentioning

confidence: 99%

Azurin-Like Protein Blocks Invasion ofToxoplasma gondiithrough Potential Interactions with Parasite Surface Antigen SAG1

Naguleswaran

Fialho

Chaudhari

et al. 2008

Antimicrob Agents Chemother

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Some pathogenic bacteria produce factors that have evolved a capacity to neutralize competing microbes. The cupredoxin family protein azurin, produced by Pseudomonas aeruginosa, exhibits a remarkable ability to impede invasion of a number of diverse intracellular pathogens, including the human AIDS virus human immunodeficiency virus type 1 and the protozoan parasite Plasmodium falciparum (which causes malaria). Here we report that azurin and an azurin-like protein (Laz) from gonococci/meningococci have activity against Toxoplasma, an apicomplexan parasite that causes opportunistic infection in immunocompromised individuals. We demonstrate that the mechanism of action for Laz involves interfering with the ability of Toxoplasma to adhere to host cells. Computer structural analysis reveals that azurin shares structural features with the predominant surface antigen SAG1, which is known to play an important role in parasite attachment. Interestingly, azurin also has structural similarities to a monoclonal antibody to SAG1. Surface plasmon resonance binding studies validate that SAG1 interacts strongly with Laz and, to lesser extent, azurin. Moreover, Toxoplasma mutants lacking SAG1 are not as susceptible to the growth-inhibitory effects of Laz. Collectively, our data show that Toxoplasma adhesion can be significantly impaired by Laz, and to some extent by azurin, via interactions with SAG1. These observations indicate that Laz can serve as an important tool in the study of host-pathogen interactions and is worthy of further study for development into potential therapeutic agents.

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The Toxoplasma surface protein SAG1 triggers efficient in vitro secretion of chemokine ligand 2 (CCL2) from human fibroblasts

Cited by 16 publications

References 33 publications

Toxoplasma gondii secretory proteins bind to sulfated heparin structures

Toxoplasma gondii secretory proteins bind to sulfated heparin structures

CCR2 Receptor Is Essential to Activate Microbicidal Mechanisms to Control Toxoplasma gondii Infection in the Central Nervous System

Azurin-Like Protein Blocks Invasion ofToxoplasma gondiithrough Potential Interactions with Parasite Surface Antigen SAG1

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