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Infection and Immunity, March 2007, p. 1223-1228, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01047-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Apoptosis-Inducing Factor Participation in Bovine Macrophage Mycobacterium bovis-Induced Caspase-Independent Cell Death

Laboratorio de Investigación en Tuberculosis Bovina, Departamento de Microbiología e Inmunología, Facultad de Medicina Veterinaria y Zootecnia,¹ Programa de Inmunología Molecular Microbiana, Facultad de Medicina,² Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico,³ Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, Texas⁴

Received 4 July 2006/ Returned for modification 25 August 2006/ Accepted 1 December 2006

Mycobacterium tuberculosis complex species survive and replicate in phagosomes of the host cell. Cell death (CD) has been highlighted as one of the probable outcomes in this host-pathogen interaction. Previously, our group demonstrated macrophage apoptosis as a consequence of Mycobacterium bovis infection. In this study, we aimed to identify the contribution of apoptotic effector elements in M. bovis-induced CD. Bovine macrophages were either infected with M. bovis (multiplicity of infection, 10:1) or treated with an M. bovis cell extract (CFE). Structural changes compatible with CD were evaluated. Chromatin condensation was increased three times by the CFE. On the other hand, a terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay demonstrated that levels of DNA fragmentation induced by M. bovis and CFE were 53.7% ± 24% and 38.9% ± 14%, respectively, whereas control cells had a basal proportion of 8.9% ± 4.1%. Rates of DNA fragmentation were unaffected by the presence of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (z-VAD). Cells treated with 100 µg of CFE for 12 h had a fivefold decrease in the level of mitochondrial outer membrane permeabilization compared to that of untreated cells. Neither M. bovis infection nor CFE treatment induced activation of caspase 3, 8, or 9. Translocation of apoptosis-inducing factor (AIF) to the nucleus was identified in 32% ± 3.5% and 26.3% ± 4.9% of M. bovis-infected and CFE-treated cells, respectively. Incubation of macrophages with z-VAD prior to infection did not alter the percentage of cells showing AIF translocation. Our data suggest that M. bovis-induced CD in bovine macrophages is caspase independent with AIF participation.

Published ahead of print on 11 December 2006.

Editor: J. L. Flynn

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