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

Hosung Sohn, Jong Seok Kim, Sung Jae Shin, Kwangwook Kim, Choul Jae Won, Woo Sik Kim, Ki Nam Min, Han Gyu Choi, Je Chul Lee, Jeong Kyu Park, Hwa Jung Kim

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33 Citations (Scopus)

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 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.

Original languageEnglish
Article numbere1002435
JournalPLoS Pathogens
Volume7
Issue number12
DOIs
Publication statusPublished - 2011 Dec

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

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    Sohn, H., Kim, J. S., Shin, S. J., Kim, K., Won, C. J., Kim, W. S., Min, K. N., Choi, H. G., Lee, J. C., Park, J. K., & Kim, H. J. (2011). Targeting of Mycobacterium tuberculosis heparin-binding hemagglutinin to mitochondria in macrophages. PLoS Pathogens, 7(12), [e1002435]. https://doi.org/10.1371/journal.ppat.1002435