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A more recent version of this article appeared on February 1, 2004
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Submitted on May 15, 2003
Revised on September 11, 2003
Accepted on October 7, 2003
1 Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center
2 Microbiology Department, Colorado State University, Fort Collins, Colorado, USA
3 Department of Molecular Genetics and Microbiology, University of New Mexico Health Sciences Center, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131, USA
* Corresponding author. E-mail address: vderetic{at}salud.unm.edu.
Mycobacterium tuberculosis is a facultative intracellular pathogen that parasitises macrophages by modulating properties of the Mycobacterium containing phagosome. Mycobacterial phagosomes do not fuse with late endosomal/lysosomal organelles, but retain access to early endosomal contents by an unknown mechanism. We have previously reported that mycobacterial phosphatidylinositol analog lipoarabinomannan (LAM) blocks a TGN-to-phagosome phosphatidylinositol 3-kinase-dependent pathway. In this work, we extend our investigations of the effects of mycobacterial phosphoinositides on host membrane trafficking. We present data demonstrating that phosphatidylinositol mannoside (PIM) specifically stimulated homotypic fusion of early endosomes in an ATP-, cytosol-, and NSF-dependent manner. The fusion showed absolute requirement for small Rab GTPases, and the stimulatory effect of PIM increased upon partial depletion of membrane Rabs with RabGDI. We also found that stimulation of early endosomal fusion by PIM was higher when phosphatidylinositol 3-kinase was inhibited by wortmannin. PIM also stimulated in vitro fusion between model phagosomes and early endosomes. Finally, PIM displayed in vivo effects in macrophages by increasing accumulation of plasma membrane-endosomal syntaxin 4 and transferrin receptor on PIM-coated latex bead phagosomes. In addition, inhibition of phagosomal acidification was detected with PIM-coated beads. The effects of PIM, along with the previously reported action of LAM, suggest that M. tuberculosis has evolved a two-prong strategy to modify its intracellular niche: its products block acquisition of late endosomal/lysosomal constituents, while facilitating fusion with early endosomal compartments.
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