Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IFN-gamma is critical for the protection against intracellular bacteria through activation of the antimicrobial machinery of phagocytes. Coxiella burnetii, the etiological agent of Q fever, is a strictly intracellular bacterium that inhabits monocytes/macrophages. We previously showed that IFN-gamma induced C. burnetii killing by promoting the apoptosis of infected monocytes. We show in this study that IFN-gamma-induced apoptosis of infected monocytes was characterized by a time- and dose-dependent activation of caspase-3. IFN-gamma-mediated caspase-3 activation and C. burnetii killing depend on the expression of membrane TNF. Indeed, TNF was transiently expressed on the cell surface of infected monocytes a few hours after IFN-gamma treatment. In addition, anti-TNF Abs inhibited IFN-gamma-mediated caspase-3 activation whereas soluble TNF had no effect on infected cells. Concomitantly, IFN-gamma induced homotypic adherence of C. burnetii-infected monocytes. The latter required the interaction of beta(2) integrins with CD54. When adherence was disrupted by pipetting, by a combination of Abs specific for CD11b, CD18, and CD54, or by an antisense oligonucleotide targeting CD18 mRNA, both cell apoptosis and bacterial killing induced by IFN-gamma were inhibited. Thus, adherence via CD54/beta(2) integrins together with membrane TNF are required to eliminate C. burnetii-infected cells through cell contact-dependent apoptosis. Our results reveal a new component of the antimicrobial arsenal mobilized by IFN-gamma against infection by intracellular bacteria.
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PMID:IFN-gamma-induced apoptosis and microbicidal activity in monocytes harboring the intracellular bacterium Coxiella burnetii require membrane TNF and homotypic cell adherence. 1244 37

Coxiella burnetii, the cause of human Q fever, is an aerosol-borne, obligate intracellular bacterium that targets host alveolar mononuclear phagocytic cells during infection. In all cell types examined, C. burnetii establishes a replicative niche in a lysosome-like parasitophorous vacuole where it carries out a lengthy infectious cycle with minimal cytopathic effects. The persistent and mild nature of C. burnetii infection in vitro suggests that the pathogen modulates apoptosis to sustain the host cell. In the current study, we examined the ability of C. burnetii to inhibit apoptotic cell death during infection of human THP-1 monocyte-derived macrophages and primary monkey alveolar macrophages. C. burnetii-infected cells demonstrated significant protection from death relative to uninfected cells following treatment with staurosporine, a potent inducer of intrinsic apoptosis. This protection correlated with reduced cleavage of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP), all proteolytic events that occur during apoptosis. Reduced PARP cleavage was also observed in cells treated with tumor necrosis factor alpha to induce extrinsic apoptosis. Apoptosis inhibition was a C. burnetii-driven process as infected cells treated with rifampin or chloramphenicol, inhibitors of bacterial RNA and protein synthesis, respectively, showed significantly reduced protection against staurosporine-induced apoptosis. C. burnetii infection affected the expression of multiple apoptosis-related genes and resulted in increased synthesis of the antiapoptotic proteins A1/Bfl-1 and c-IAP2. Collectively, these data suggest that C. burnetii modulates apoptotic pathways to inhibit host cell death, thus providing a stable, intracellular niche for the course of the pathogen's infectious cycle.
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PMID:Coxiella burnetii inhibits apoptosis in human THP-1 cells and monkey primary alveolar macrophages. 1760 99

Coxiella burnetii is an obligate intracellular pathogen and the etiological agent of the human disease Q fever. C. burnetii infects mammalian cells and then remodels the membrane-bound compartment in which it resides into a unique lysosome-derived organelle that supports bacterial multiplication. To gain insight into the mechanisms by which C. burnetii is able to multiply intracellularly, we examined the ability of host cells to respond to signals that normally induce apoptosis. Our data show that mammalian cells infected with C. burnetii are resistant to apoptosis induced by staurosporine and UV light. C. burnetii infection prevented caspase 3/7 activation and limited fragmentation of the host cell nucleus in response to agonists that induce apoptosis. Inhibition of bacterial protein synthesis reduced the antiapoptotic effect that C. burnetii exerted on infected host cells. Inhibition of apoptosis in C. burnetii-infected cells did not correlate with the degradation of proapoptotic BH3-only proteins involved in activation of the intrinsic cell death pathway; however, cytochrome c release from mitochondria was diminished in cells infected with C. burnetii upon induction of apoptosis. These data indicate that C. burnetii can interfere with the intrinsic cell death pathway during infection by producing proteins that either directly or indirectly prevent release of cytochrome c from mitochondria. It is likely that inhibition of apoptosis by C. burnetii represents an important virulence property that allows this obligate intracellular pathogen to maintain host cell viability despite inducing stress that would normally activate the intrinsic death pathway.
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PMID:Coxiella burnetii inhibits activation of host cell apoptosis through a mechanism that involves preventing cytochrome c release from mitochondria. 1770 6