Interactions of Attenuated Mycobacterium Tuberculosis phoP Mutant With Human Macrophages

PLoS One. 2010 Sep 24;5(9):e12978. doi: 10.1371/journal.pone.0012978.

Abstract

Background: Mycobacterium tuberculosis phoP mutant SO2 derived from a clinical isolate was shown to be attenuated in mouse bone marrow-derived macrophages and in vivo mouse infection model and has demonstrated a high potential as attenuated vaccine candidate against tuberculosis.

Methodology/principal findings: In this study, we analyze the adhesion and the intracellular growth and trafficking of SO2 in human macrophages. Our results indicate an enhanced adhesion to phagocitic cells and impaired intracellular replication of SO2 in both monocyte-derived macrophages and human cell line THP-1 in comparison with the wild type strain, consistent with murine model. Intracellular trafficking analysis in human THP-1 cells suggest that attenuation of SO2 within macrophages could be due to an impaired ability to block phagosome-lysosome fusion compared with the parental M. tuberculosis strain. No differences were found between SO2 and the wild-type strains in the release and mycobacterial susceptibility to nitric oxide (NO) produced by infected macrophages.

Conclusions/significance: SO2 has enhanced ability to bind human macrophages and differs in intracellular trafficking as to wild-type M. tuberculosis. The altered lipid profile expression of the phoP mutant SO2 and its inability to secrete ESAT-6 is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Cell Adhesion*
  • Cell Line
  • Cells, Cultured
  • Humans
  • Macrophages / immunology
  • Macrophages / microbiology*
  • Mice
  • Monocytes / microbiology
  • Mutation*
  • Mycobacterium tuberculosis / genetics
  • Mycobacterium tuberculosis / physiology*
  • Tuberculosis / immunology
  • Tuberculosis / microbiology*
  • Tuberculosis Vaccines / genetics
  • Tuberculosis Vaccines / immunology
  • Vaccines, Attenuated / genetics
  • Vaccines, Attenuated / immunology

Substances

  • Bacterial Proteins
  • Tuberculosis Vaccines
  • Vaccines, Attenuated
  • PhoP protein, Bacteria