Dec 17, 2011

Targeting of Mycobacterium tuberculosis heparin-binding hemagglutinin to mitochondria in macrophages

PLoS Pathogens
Hosung SohnHwa-Jung Kim

Abstract

Mycobacterium tuberculosis heparin-binding hemagglutinin (HBHA), a virulence factor involved in extrapulmonary dissemination and a strong diagnostic antigen against tuberculosis, is both surface-associated and secreted. The role of HBHA in macrophages during M. tuberculosis infection, however, is less well known. Here, we show that recombinant HBHA produced by Mycobacterium smegmatis effectively induces apoptosis in murine macrophages. DNA fragmentation, nuclear condensation, caspase activation, and poly (ADP-ribose) polymerase cleavage were observed in apoptotic macrophages treated with HBHA. Enhanced reactive oxygen species (ROS) production and Bax activation were essential for HBHA-induced apoptosis, as evidenced by a restoration of the viability of macrophages pretreated with N-acetylcysteine, a potent ROS scavenger, or transfected with Bax siRNA. HBHA is targeted to the mitochondrial compartment of HBHA-treated and M. tuberculosis-infected macrophages. Dissipation of the mitochondrial transmembrane potential (ΔΨ(m)) and depletion of cytochrome c also occurred in both macrophages and isolated mitochondria treated with HBHA. Disruption of HBHA gene led to the restoration of ΔΨ(m) impairment in infected macrophages, resulting...Continue Reading

Mentioned in this Paper

Pathologic Cytolysis
Caspase-9
Establishment and Maintenance of Localization
Mitochondrial Toxicity
Pathogenic Aspects
Flow Cytometry
Biochemical Pathway
Amidophosphoribosyltransferase
HbhA protein, Mycobacterium tuberculosis
Necrosis

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