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Infection and Immunity, September 2005, p. 5504-5513, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5504-5513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mannheimia haemolytica Leukotoxin Induces Apoptosis of Bovine Lymphoblastoid Cells (BL-3) via a Caspase-9-Dependent Mitochondrial Pathway

Dhammika N. Atapattu and Charles J. Czuprynski*

Department of Pathobiological Sciences, University of Wisconsin, School of Veterinary Medicine, Madison, Wisconsin

Received 11 February 2005/ Returned for modification 8 April 2005/ Accepted 3 May 2005

Mannheimia haemolytica is a key pathogen in the bovine respiratory disease complex. It produces a leukotoxin (LKT) that is an important virulence factor, causing cell death in bovine leukocytes. The LKT binds to the ß2 integrin CD11a/CD18, which usually activates signaling pathways that facilitate cell survival. In this study, we investigated mechanisms by which LKT induces death in bovine lymphoblastoid cells (BL-3). Incubation of BL-3 cells with a low concentration of LKT results in the activation of caspase-3 and caspase-9 but not caspase-8. Similarly, the proapoptotic proteins Bax and BAD were significantly elevated, while the antiapoptotic proteins Bcl-2, BclXL and Akt-1 were downregulated. Following exposure to LKT, we also observed a reduction in mitochondrial cytochrome c and corresponding elevation of cytosolic cytochrome c, suggesting translocation from the mitochondrial compartment to the cytosol. Consistent with this observation, tetramethylrhodamine ethyl ester perchlorate staining revealed that mitochondrial membrane potential was significantly reduced. These data suggest that LKT induces apoptosis of BL-3 cells via a caspase-9-dependent mitochondrial pathway. Furthermore, scanning electron micrographs of mitochondria from LKT-treated BL-3 cells revealed lesions in the outer mitochondrial membrane, which are larger than previous reports of the permeability transition pore through which cytochrome c is usually released.

* Corresponding author. Mailing address: Department of Pathobiological Sciences, University of Wisconsin, School of Veterinary Medicine, 2015 Linden Dr. West, Madison, WI 53706. Phone: (608) 262-8102. Fax: (608) 262-8102. E-mail: czuprync{at}svm.vetmed.wisc.edu.

Editor: J. T. Barbieri

Infection and Immunity, September 2005, p. 5504-5513, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5504-5513.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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