IFN-gamma-induced apoptosis and microbicidal activity in monocytes harboring the intracellular bacterium Coxiella burnetii require membrane TNF and homotypic cell adherence

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...

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Published in:The Journal of immunology (1950) 2002-12, Vol.169 (11), p.6309-6315
Main Authors: Dellacasagrande, Jérôme, Ghigo, Eric, Raoult, Didier, Capo, Christian, Mege, Jean-Louis
Format: Article
Language:English
Subjects:
Apoptosis
Caspase 3
Caspases - metabolism
CD18 Antigens - metabolism
Cell Adhesion
Cell Line
Cell Membrane - immunology
Coxiella burnetii - immunology
Coxiella burnetii - pathogenicity
Cytotoxicity, Immunologic
Enzyme Activation
Humans
Interferon-gamma - metabolism
Interferon-gamma - pharmacology
Monocytes - drug effects
Monocytes - immunology
Monocytes - microbiology
Monocytes - pathology
Recombinant Proteins
Tumor Necrosis Factor-alpha - metabolism
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.169.11.6309