title: A mechanism of virulence: virulent Mycobacterium tuberculosis strain H37Rv, but not attenuated H37Ra, causes significant mitochondrial inner membrane disruption in macrophages leading to necrosis.
abstract: Infection of human monocyte-derived macrophages with Mycobacterium tuberculosis at low multiplicities of infection leads 48-72 h after the infection to cell death with the characteristics of apoptosis or necrosis. Predominant induction of one or the other cell death modality depends on differences in mitochondrial membrane perturbation induced by attenuated and virulent strains. Infection of macrophages with the attenuated H37Ra or the virulent H37Rv causes mitochondrial outer membrane permeabilization characterized by cytochrome c release from the mitochondrial intermembrane space and apoptosis. Mitochondrial outer membrane permeabilization is transient, peaks 6 h after infection, and requires Ca(2+) flux and B cell chronic lymphocytic leukemia/lymphoma 2-associated protein X translocation into mitochondria. In contrast, only the virulent H37Rv induces significant mitochondrial transmembrane potential (Deltapsi(m)) loss caused by mitochondrial permeability transition. Dissipation of Deltapsi(m) also peaks at 6 h after infection, is transient, is inhibited by the classical mitochondrial permeability transition inhibitor cyclosporine A, has a requirement for mitochondrial Ca(2+) loading, and is independent of B cell chronic lymphocytic leukemia/lymphoma translocation into the mitochondria. Transient dissipation of Deltapsi(m) 6 h after infection is essential for the induction of macrophage necrosis by Mtb, a mechanism that allows further dissemination of the pathogen and development of the disease.
authors.affiliation: Division of Rheumatology/Immunology, Department of Medicine, Medical Research Center Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
authors.forename: Minjian
authors.initials: M
authors.lastname: Chen
authors.forename: Huixian
authors.initials: H
authors.lastname: Gan
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Remold
mesh_terms: D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002413:Cations, Divalent / Q000737:chemistry; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology*; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000378:metabolism / Q000382:microbiology / Q000473:pathology*; D009169:Mycobacterium tuberculosis / Q000145:classification* / Q000472:pathogenicity*; D009336:Necrosis; D014774:Virulence; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D002413:Cations, Divalent; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D002118:Calcium