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A Mycobacterium tuberculosis-Derived Lipid Inhibits Membrane Fusion by Modulating Lipid Membrane Domains

Eri Hayakawa ^* , Fuyuki Tokumasu , Glenn A. Nardone , Albert J. Jin , Vince A. Hackley ^¶ and James A. Dvorak 

^* Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8, Honcho, Kawaguchi, Saitama, 332-0012, Japan; Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases; Research Technology Branch, National Institute of Allergy and Infectious Diseases; and Division of Bioengineering and Physical Science, ORS/OD, National Institutes of Health, Bethesda, Maryland 20892-5766; and ^¶ Materials Science and Engineering Laboratory, National Institute of Standards and Technology, Gaithersburg, Maryland 20899-8520

Correspondence: Address reprint requests to Fuyuki Tokumasu, Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Room 2W-09B Twinbrook III, 12735 Twinbrook Parkway, Bethesda, MD 20892-8132. Tel.: 301-451-1224; Fax: 301-480-1438; E-mail: ftokumasu{at}niaid.nih.gov.

Tuberculosis is an infectious and potentially fatal disease caused by the acid-fast bacillus Mycobacterium tuberculosis (MTB). One hallmark of a tuberculosis infection is the ability of the bacterium to subvert the normal macrophage defense mechanism of the host immune response. Lipoarabinomannan (LAM), an integral component of the MTB cell wall, is released when MTBs are taken into phagosomes and has been reported to be involved in the inhibition of phago-lysosomal (P-L) fusion. However, the physical chemistry of the effects of LAM on lipid membrane structure relative to P-L fusion has not been studied. We produced membranes in vitro composed of dioleoylphosphatidylcholine, sphingomyelin, and cholesterol to simulate phagosomal lipid membranes and quantified the effects of the addition of LAM to these membranes, using fluorescence resonance energy transfer assays and atomic force microscopy. We found that LAM inhibits vesicle fusion and markedly alters lipid membrane domain morphology and sphingomyelin-chollesterol/dioleoylphosphatidylcholine ratios. These data demonstrate that LAM induces a dramatic reorganization of lipid membranes in vitro and clarifies the role of LAM in the inhibition of P-L fusion and the survival of the MTB within the macrophage.

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