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The Journal of Immunology, 2002, 169: 6309-6315.
Copyright © 2002 by The American Association of Immunologists

IFN-{gamma}-Induced Apoptosis and Microbicidal Activity in Monocytes Harboring the Intracellular Bacterium Coxiella burnetii Require Membrane TNF and Homotypic Cell Adherence1

Jérôme Dellacasagrande2, Eric Ghigo, Didier Raoult, Christian Capo and Jean-Louis Mege

Unité des Rickettsies, Unité Mixte de Recherche 6020, Centre National de la Recherche Scientifique, Faculté de Médecine, Université de la Méditerranée, Marseille, France

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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