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Vaccinia virus induces apoptosis of infected macrophages

Zora Mlková¹

Department of Pathological Physiology, Charles University, 1^st Medical Faculty, U nemocnice 5, 128 53, Prague 2, Czech Republic
Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain²

Author for correspondence: Zora Mlková. Present address: Department of Immunology and Microbiology, Charles University, 1^st Medical Faculty, Studnikova 7, 128 00, Prague 2, Czech Republic. Fax +420 2 2491 3110. e-mail zmelk{at}lf1.cuni.cz

Vaccinia virus (VV) infects a broad range of host cells, and while it usually causes their lysis (i.e. necrosis), the nature of the cell-death phenomenon is not well understood. In this study, we show that VV induces apoptosis of cells of the murine macrophage line J774.G8, as revealed by morphological signs, DNA ladder formation, changes of mitochondrial membrane potential and annexin-V positivity. Apoptosis occurred in both untreated and IFN--pretreated macrophages, and could not be inhibited by aminoguanidine, a relatively specific inhibitor of inducible nitric oxide synthase. Inhibition of VV DNA synthesis and late gene expression by cytosine arabinoside also did not prevent apoptosis, while heat- or psoralen/UV-inactivated VV did not cause any apoptosis. Thus, VV early gene expression seems to be required for induction of apoptosis. At the cellular level, infection with VV induced a decrease in the levels of Bcl-x_L, an anti-apoptotic member of the Bcl-2 family. The importance of loss of Bcl-x_L was demonstrated by prevention of VV-mediated apoptosis on expression of Bcl-2, a functional homologue of Bcl-x_L. Our findings provide evidence that induction of apoptosis by VV in macrophages requires virus early gene expression, does not involve nitric oxide, induces a decrease in mitochondrial membrane potential and is associated with altered levels of Bcl-x_L.

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