The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published 3 October 2005. doi:10.1084/jem.20051239
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 7, 987-999
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ARTICLE

 The human macrophage mannose receptor directs Mycobacterium tuberculosis lipoarabinomannan-mediated phagosome biogenesis

Peter B. Kang2, Abul K. Azad1, Jordi B. Torrelles1, Thomas M. Kaufman2, Alison Beharka2, Eric Tibesar2, Lucy E. DesJardin2, and Larry S. Schlesinger1

1 Division of Infectious Diseases, Departments of Internal Medicine and Molecular Virology, Immunology, and Medical Genetics, and the Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210
2 Division of Infectious Diseases, Departments of Internal Medicine and Microbiology, the Immunology Program, and the VA Medical Center, The University of Iowa, Iowa City, IA 52242

CORRESPONDENCE Larry S. Schlesinger: schlesinger-2{at}medctr.osu.edu

Mycobacterium tuberculosis (M.tb) survives in macrophages in part by limiting phagosome–lysosome (P-L) fusion. M.tb mannose-capped lipoarabinomannan (ManLAM) blocks phagosome maturation. The pattern recognition mannose receptor (MR) binds to the ManLAM mannose caps and mediates phagocytosis of bacilli by human macrophages. Using quantitative electron and confocal microscopy, we report that engagement of the MR by ManLAM during the phagocytic process is a key step in limiting P-L fusion. P-L fusion of ManLAM microspheres was significantly reduced in human macrophages and an MR-expressing cell line but not in monocytes that lack the receptor. Moreover, reversal of P-L fusion inhibition occurred with MR blockade. Inhibition of P-L fusion did not occur with entry via Fc{gamma} receptors or dendritic cell–specific intracellular adhesion molecule 3 grabbing nonintegrin, or with phosphatidylinositol-capped lipoarabinomannan. The ManLAM mannose cap structures were necessary in limiting P-L fusion, and the intact molecule was required to maintain this phenotype. Finally, MR blockade during phagocytosis of virulent M.tb led to a reversal of P-L fusion inhibition in human macrophages (84.0 ± 5.1% vs. 38.6 ± 0.6%). Thus, engagement of the MR by ManLAM during the phagocytic process directs M.tb to its initial phagosomal niche, thereby enhancing survival in human macrophages.

Abbreviations used: DC-SIGN, DC-specific intracellular adhesion molecule 3 grabbing nonintegrin; dManLAM, deacylated ManLAM; HSA, human serum albumin; LM, lipomannan; ManLAM, mannose-capped lipoarabinomannan; MDM, monocyte-derived macrophages; MOI, multiplicity of infection; MR, mannose receptor; M.tb, Mycobacterium tuberculosis; PILAM, phosphatidyl-myo-inositol capped lipoarabinomannan; P-L, phagosome–lysosome; PRR, pattern recognition receptor; TEM, transmission electron microscopy.

P.B. Kang and A.K. Azad contributed equally to this work.

P.B. Kang's present address is Division of Science and Research Institute, American Dental Association, Chicago, IL 60611.

L.E. DesJardin's present address is University Hygienic Laboratory, University of Iowa, Iowa City, IA 52242.


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