<i>Toxoplasma gondii</i>infection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax

Hippe, Diana; Weber, Arnim; Zhou, Lei; Chang, Donald C.; Häcker, Georg; Lüder, Carsten G. K.

doi:10.1242/jcs.050963

Cited by 38 publications

(31 citation statements)

References 48 publications

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“…1C) and was completely abolished by 1 × 10 8 parasites per ml of cytosolic host cell extract. Thus, T. gondii is able to inhibit activation of the caspase 9-caspase 3 cascade independently of its effect on MOMP 3037.…”

Section: Resultsmentioning

confidence: 96%

“…It was therefore critical to assess whether T. gondii also directly interferes with cytochrome c -induced caspase activation when being confined to its natural intracellular habitat. In order to distinguish between the parasite-mediated inhibition of cytochrome c release from mitochondria as described previously 3037 and the mechanism described herein in infected cells, we measured the caspase 3/7 activity which had been induced in cytosolic extracts from non-infected and T. gondii -infected Jurkat cells after addition of cytochrome c and dATP. The results showed that infection with T. gondii for 24 hours dose-dependently reduced such DEVD-AMC cleavage activity (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Importantly, during Toxoplasma encephalitis in mice, parasite-infected host cells are also protected from undergoing inflammation-associated PCD 3536. Release of cytochrome c from mitochondria to the host cell cytosol is profoundly decreased in parasite-positive cells 3032 and this is at least in part due to reduced activation of the pro-apoptotic Bcl-2 effector protein Bax 37. Activation of NF-κB 3138 and protein kinase B/Akt 33 may function as upstream signaling pathways contributing to the block of caspase-dependent intrinsic cell death in infected cells.…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Graumann

Schaumburg

Reubold

et al. 2015

MIC

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Inhibition of programmed cell death pathways of mammalian cells often facilitates the sustained survival of intracellular microorganisms. The apicomplexan parasite Toxoplasma gondii is a master regulator of host cell apoptotic pathways. Here, we have characterized a novel anti-apoptotic activity of T. gondii. Using a cell-free cytosolic extract model, we show that T. gondii interferes with the activities of caspase 9 and caspase 3/7 which have been induced by exogenous cytochrome c and dATP. Proteolytic cleavage of caspases 9 and 3 is also diminished suggesting inhibition of holo-apoptosome function. Parasite infection of Jurkat T cells and subsequent triggering of apoptosome formation by exogenous cytochrome c in vitro and in vivo indicated that T. gondii also interferes with caspase activation in infected cells. Importantly, parasite inhibition of cytochrome c-induced caspase activation considerably contributes to the overall anti-apoptotic activity of T. gondii as observed in staurosporine-treated cells. Co-immunoprecipitation showed that T. gondii abolishes binding of caspase 9 to Apaf-1 whereas the interaction of cytochrome c with Apaf-1 remains unchanged. Finally, T. gondii lysate mimics the effect of viable parasites and prevents holo-apoptosome functionality in a reconstituted in vitro system comprising recombinant Apaf-1 and caspase 9. Beside inhibition of cytochrome c release from host cell mitochondria, T. gondii thus also targets the holo-apoptosome assembly as a second mean to efficiently inhibit the caspase-dependent intrinsic cell death pathway.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Graumann

Schaumburg

Reubold

et al. 2015

MIC

Self Cite

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“…A number of pathogens have been shown to inhibit host cell apoptosis modulating several survival mechanisms [19][20][21][22][23]. It is well known that apoptosis signaling of a cell can be divided into two pathways, which results into similar outcome, that is, downstream caspase activation and cell death.…”

Section: Introductionmentioning

confidence: 99%

Infection of neutrophil granulocytes with Leishmania major activates ERK 1/2 and modulates multiple apoptotic pathways to inhibit apoptosis

Sarkar

Aga

Bussmeyer

et al. 2012

Med Microbiol Immunol

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Neutrophil granulocytes provide the first line of defense against bacterial, fungal, and parasitic infections. They phagocytose and kill many invading pathogens. Certain pathogenic microorganisms such as the intracellular protozoan parasite Leishmania major (L. major) can survive inside neutrophils. Mature neutrophils have a very short life span due to spontaneous apoptosis. Previously, we have reported that infections with L. major are able to delay spontaneous apoptosis. In the present study, we addressed the underlying mechanisms of regulation of both extrinsic and intrinsic apoptosis. We show that interaction with L. major transiently activates ERK1/2 phosphorylation. Pharmacological inhibition of ERK1/2 phosphorylation reversed the apoptosis delay. Moreover, infection leads to the enhanced and sustainable expression of the anti-apoptotic proteins Bcl-2 and Bfl-1, respectively. As downstream events, the release of cytochrome c from mitochondria and processing of caspase-6 were inhibited. We also confirm that infection with L. major results in reduced FAS expression on the surface of neutrophils. The presented data indicate that infection with L. major affects both intrinsic as well as extrinsic pathways of neutrophil apoptosis. Enhanced life span of host neutrophils enables the parasite to survive within neutrophils.

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“…The anti-apoptotic proteins Bcl-2 and Bcl-X L have been shown to both prevent disruption of mitochondrial physiology and block cytochrome c release from mitochondria (Kroemer 2003;Scorrano and Korsmeyer 2003). A large volume of literature has addressed the mechanisms of apoptosis; and several reports have been reported that T. gondii inhibits the release of cytochrome c from host cell mitochondria (Carmen et al 2006;Goebel et al 2001;Hippe et al 2009). Intracellular pathogens have evolved diverse strategies to avoid destruction by the host immune response.…”

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii infection inhibits the mitochondrial apoptosis through induction of Bcl-2 and HSP70

et al. 2010

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Heat-shock protein 70 (HSP70) is highly expressed in Toxoplasma gondii-infected cells. However, the role of this protein is not well understood, especially during apoptosis. This study addresses the mechanism behind the antiapoptotic chaperone activity of HSP70 in Toxoplasma-infected host cells using a human macrophage cell line, THP-1 by Western blot, DNA fragmentation assay, immunoprecipitation, and a caspase-3/7 activity assay based on cleavage of the colorimetric substrate DEVD-pNA. Apoptosis induced by arsenic trioxide (As(2)O(3)) was inhibited in T. gondii-infected THP-1 cells, but not in uninfected cells. Without As(2)O(3) induction of apoptosis, T. gondii infection caused increased expression of Bcl-2 and HSP70, but not caspase-3. However, active form caspase-3 levels were lower in As(2)O(3)-treated infected cells as compared with As(2)O(3)-treated uninfected cells. Bcl-2 expression in As(2)O(3)-treated infected cells was similar to that in cells infected with T. gondii. Translocation of apoptosis-inducing factor (AIF) and release of cytochrome c from mitochondria were inhibited in As(2)O(3)-treated infected cells as compared with As(2)O(3)-treated uninfected cells. Increased parasite loads in Toxoplasma-infected macrophages caused higher HSP70 and Bcl-2 expression in whole-cell extracts and fractionated components, respectively. However, expression of AIF and cytochrome c was unaffected. Toxoplasma dose-dependently inhibited caspase-3 activation, thus revealing an anti-apoptotic parasite activity on cytochrome c-mediated caspase activation in subcellular components. In addition, immunoprecipitation analysis suggested that HSP70 is capable of binding to the pro-apoptotic factors AIF and Apaf-1, but not to cytochrome c or procaspase-9. Taken together, these data demonstrate that T. gondii infection inhibits mitochondrial apoptosis through overproduction of anti-apoptotic Bcl-2 as well as HSP70, which are increased parasite loads dependently.

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Toxoplasma gondiiinfection confers resistance against BimS-induced apoptosis by preventing the activation and mitochondrial targeting of pro-apoptotic Bax

Cited by 38 publications

References 48 publications

Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Toxoplasma gondii inhibits cytochrome c-induced caspase activation in its host cell by interference with holo-apoptosome assembly

Infection of neutrophil granulocytes with Leishmania major activates ERK 1/2 and modulates multiple apoptotic pathways to inhibit apoptosis

Toxoplasma gondii infection inhibits the mitochondrial apoptosis through induction of Bcl-2 and HSP70

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