Targeting of Mycobacterium tuberculosis Heparin-Binding Hemagglutinin to Mitochondria in Macrophages

PLoS Pathogens

Je Chul Lee¹  Sung Jae Shin²  Kwangwook Kim²  Woo Sik Kim²  Jeong-Kyu Park²  Han-Gyu Choi²  Ki-Nam Min²  Hosung Sohn²  Choul-Jae Won²  Jong-Seok Kim²  Hwa-Jung Kim² 

[1] Department of Microbiology, Kyungpook National University School of Medicine, Daegu, South Korea;Department of Microbiology, Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon, South Korea

关键词: Mitochondria;    Apoptosis;    Mycobacterium tuberculosis;    Macrophages;    DNA fragmentation;    Host cells;    Enzyme-linked immunoassays;    Flow cytometry;   

DOI  :  10.1371/journal.ppat.1002435

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 (ΔΨm) 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 ΔΨm impairment in infected macrophages, resulting in reduced apoptosis. Taken together, our data suggest that HBHA may act as a strong pathogenic factor to cause apoptosis of professional phagocytes infected with M. tuberculosis.

【 授权许可】

CC BY