Host cell Ca2+ and protein kinase C regulate innate recognition of<i>Toxoplasma gondii</i>

Masek, Katherine S.; Fiore, Jim; Leitges, Michael; Yan, Shi‐Fang; Freedman, Bruce D.; Hunter, Christopher A.

doi:10.1242/jcs.03206

Cited by 26 publications

(19 citation statements)

References 69 publications

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“…Because some of these pathways are also implicated in stimulating EGR-dependent transcription (31, 71), we sought to determine what role, if any, they played in Toxoplasma induction of EGR2. To specifically inhibit host cell Ca 2ϩ signaling during Toxoplasma infection, we pretreated host cells with BAPTA-AM and then extensively washed the cells before infecting them with parasites in BAPTA-AM-free medium (43). EGR2 mRNA levels measured 6 h postinfection indicated that chelating host cell intracellular calcium increased Toxoplasma-stimulated EGR2 expression with marginal statistical significance (Student's t test; P ϭ 0.058) (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Increases in intracellular Ca 2ϩ levels as well as activation of MAPKs (p38, extracellular signalregulated kinase [ERK], and c-jun N-terminal protein kinase) and phosphoinositide-3 kinase (PtdIns-3K) are signaling events triggered in Toxoplasma-infected cells (33,34,43). Because some of these pathways are also implicated in stimulating EGR-dependent transcription (31, 71), we sought to determine what role, if any, they played in Toxoplasma induction of EGR2.…”

Section: Resultsmentioning

confidence: 99%

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Toxoplasma gondiiRhoptry Discharge Correlates with Activation of the Early Growth Response 2 Host Cell Transcription Factor

2008

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Toxoplasma gondii is a ubiquitous apicomplexan parasite that can cause severe disease in fetuses and immune-compromised patients. Rhoptries, micronemes, and dense granules, which are secretory organelles unique to Toxoplasma and other apicomplexan parasites, play critical roles in parasite growth and virulence. To understand how these organelles modulate infected host cells, we sought to identify host cell transcription factors triggered by their release. Early growth response 2 (EGR2) is a host cell transcription factor that is rapidly upregulated and activated in Toxoplasma-infected cells but not in cells infected with the closely related apicomplexan parasite Neospora caninum. EGR2 upregulation occurred only when live parasites were in direct contact with the host cell and not from exposure to cell extracts that contain dense granule or micronemal proteins. When microneme-mediated attachment was blocked by pretreating parasites with a calcium chelator, EGR2 expression was significantly reduced. In contrast, when host cells were infected with parasites in the presence of cytochalasin D, which allows rhoptry secretion but prevents parasite invasion, EGR2 was activated. Finally, we demonstrate that Toxoplasma activation of host p38 mitogen-activated protein kinase is necessary but not sufficient for EGR2 activation. Collectively, these data indicate that EGR2 is specifically upregulated by a parasite-derived secreted factor that is most likely a resident rhoptry protein.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Toxoplasma gondiiRhoptry Discharge Correlates with Activation of the Early Growth Response 2 Host Cell Transcription Factor

2008

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“…These data agree with other experimental models that demonstrated that NO is not detected in large amounts in human systems. 49 The low parasitism observed in the first-trimester explant experiments may be related to a particular role of MIF that mediates a proinflammatory profile after stimulus in the presence of immunosuppressive hormones. 39 Alternatively, in thirdtrimester placental explants, MIF controlled T. gondii infection only at the highest concentration of this cytokine.…”

Section: Discussionmentioning

confidence: 99%

Effect of Macrophage Migration Inhibitory Factor (MIF) in Human Placental Explants Infected with Toxoplasma gondii Depends on Gestational Age

Gomes¹,

Silva²,

Silva³

et al. 2011

The American Journal of Pathology

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Because macrophage migration inhibitory factor (MIF) is a key cytokine in pregnancy and has a role in inflammatory response and pathogen defense, the objective of the present study was to investigate the effects of MIF in first-and third-trimester human placental explants infected with Toxoplasma gondii. Explants were treated with recombinant MIF, IL-12, interferon-␥, transforming growth factor-␤1, or IL-10, followed by infection with T. gondii RH strain tachyzoites. Supernatants of cultured explants were assessed for MIF production. Explants were processed for morphologic analysis, immunohistochemistry, and real-time PCR analysis. Comparison of infected and stimulated explants versus noninfected control explants demonstrated a significant increase in MIF release in first-trimester but not third-trimester explants. Tissue parasitism was higher in third-than in first-trimester explants. Moreover, T. gondii DNA content was lower in first-trimester explants treated with MIF compared with untreated explants. However, in third-trimester explants, MIF stimulus decreased T. gondii DNA content only at the highest concentration of the cytokine. In addition, high expression of MIF receptor was observed in first-trimester placental explants, whereas MIF receptor expression was low in third-trimester explants. In conclusion, MIF was up-regulated and demonstrated to be important for control of T. gondii infection in first-trimester explants, whereas lack of MIF up-regulation in third-trimester placentas may be involved in higher susceptibility to infection at this gestational age.

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“…Interestingly, PKC is suggested to act as a critical regulatory kinase in the initiation of diverse innate immune responses (33). Furthermore, identification of signaling partners of the NOD2-iNOS-Notch1-PI3K axis that are critical in driving the expression of anti-inflammatory molecular signatures, assumes novel significance.…”

Section: Inos/no Axis Is An Essential Link In Nod2-driven Notch1mentioning

confidence: 99%

Intracellular Pathogen Sensor NOD2 Programs Macrophages to Trigger Notch1 Activation

Bansal¹,

Balaji

2011

Journal of Biological Chemistry

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Host cell Ca2+ and protein kinase C regulate innate recognition ofToxoplasma gondii

Abstract: There was an error published in J. Cell Sci. 119, 4565-4573.In Fig. 7C, the 1 mM and 5 mM bars were incorrectly labelled. The corrected figure and legend are shown below. The authors apologise for this error.

Cited by 26 publications

References 69 publications

Toxoplasma gondiiRhoptry Discharge Correlates with Activation of the Early Growth Response 2 Host Cell Transcription Factor

Toxoplasma gondiiRhoptry Discharge Correlates with Activation of the Early Growth Response 2 Host Cell Transcription Factor

Effect of Macrophage Migration Inhibitory Factor (MIF) in Human Placental Explants Infected with Toxoplasma gondii Depends on Gestational Age

Intracellular Pathogen Sensor NOD2 Programs Macrophages to Trigger Notch1 Activation

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