title: Production of phthiocerol dimycocerosates protects Mycobacterium tuberculosis from the cidal activity of reactive nitrogen intermediates produced by macrophages and modulates the early immune response to infection.
abstract: The growth of Mycobacterium tuberculosis mutants unable to synthesize phthiocerol dimycocerosates (DIMs) was recently shown to be impaired in mouse lungs. However, the precise role of these molecules in the course of infection remained to be determined. Here, we provide evidence that the attenuation of a DIM-deficient strain takes place during the acute phase of infection in both lungs and spleen of mice, and that this attenuation results in part from the increased sensitivity of the mutant to the cidal activity of reactive nitrogen intermediates released by activated macrophages. We also show that the DIM-deficient mutant, the growth and survival of which were not impaired within resting macrophages and dendritic cells, induced these cells to secrete more tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 than the wild-type strain. Although purified DIM molecules by themselves had no effect on the activation of macrophages and dendritic cells in vitro, we found that the proper localization of DIMs in the cell envelope of M. tuberculosis is critical to their biological effects. Thus, our findings suggest that DIM production contributes to the initial growth of M. tuberculosis by protecting it from the nitric oxide-dependent killing of macrophages and modulating the early immune response to infection.
authors.affiliation: Unité de Génétique Mycobactérienne, Institut Pasteur, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Rousseau
authors.forename: Nathalie
authors.initials: N
authors.lastname: Winter
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pivert
authors.forename: Yann
authors.initials: Y
authors.lastname: Bordat
authors.forename: Olivier
authors.initials: O
authors.lastname: Neyrolles
authors.forename: Patrick
authors.initials: P
authors.lastname: Avé
authors.forename: Michel
authors.initials: M
authors.lastname: Huerre
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gicquel
authors.forename: Mary
authors.initials: M
authors.lastname: Jackson
mesh_terms: D000818:Animals; D004347:Drug Interactions; D007107:Immune System / Q000187:drug effects*; D008055:Lipids / Q000494:pharmacology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000737:chemistry* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects* / Q000254:growth & development; D026361:Reactive Nitrogen Species / Q000494:pharmacology*; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology
chemical_list: D008055:Lipids; D026361:Reactive Nitrogen Species; C008901:phthiocerol dimycocerosate