Delay of phagosome maturation by a mycobacterial lipid is reversed by nitric oxide.
Mycobacterium tuberculosis is a facultative intracellular pathogen that inhibits phagosome maturation in macrophages thereby securing survival and growth. Mycobacteria reside in an early endocytic compartment of near-neutral pH where they upregulate production of complex glycolipids such as trehalose dimycolate. Here, we report that trehalose dimycolate coated onto beads increased the bead retention in early phagosomes, i.e. at a similar stage as viable mycobacteria. Thus, a single mycobacterial lipid sufficed to divert phagosome maturation and likely contributes to mycobacterial survival in macrophages. Previous studies showed that activated macrophages promote maturation of mycobacterial phagosomes and eliminate mycobacteria through bactericidal effectors including nitric oxide generated by inducible nitric-oxide synthase. We show that deceleration of bead phagosome maturation by trehalose dimycolate was abolished in immune-activated wild type, but not in activated nitric-oxide synthase-deficient macrophages, nor when hydroxyl groups of trehalose dimycolate were chemically modified by reactive nitrogen intermediates. Thus, specific host defence effectors of activated macrophages directly target a specific virulence function of mycobacteria.
Axelrod
Sofia
S
Department of Immunology, Max Planck Institute for Infection Biology, D-10117 Berlin, Germany.
Oschkinat
Hartmut
H
Enders
Jana
J
Schlegel
Brigitte
B
Brinkmann
Volker
V
Kaufmann
Stefan H E
SH
Haas
Albert
A
Schaible
Ulrich E
UE
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003311:Cord Factors / Q000737:chemistry / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018189:Immunomagnetic Separation; D007371:Interferon-gamma / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008981:Molsidomine / Q000031:analogs & derivatives / Q000378:metabolism; D009161:Mycobacterium / Q000276:immunology* / Q000472:pathogenicity; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D010588:Phagosomes / Q000378:metabolism* / Q000648:ultrastructure; D026361:Reactive Nitrogen Species / Q000378:metabolism
D000276:Adjuvants, Immunologic; D003311:Cord Factors; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D026361:Reactive Nitrogen Species; D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; C002385:linsidomine; D007371:Interferon-gamma; D008981:Molsidomine; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse