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.
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.
Rousseau
Cécile
C
Unité de Génétique Mycobactérienne, Institut Pasteur, Paris, France.
Winter
Nathalie
N
Pivert
Elisabeth
E
Bordat
Yann
Y
Neyrolles
Olivier
O
Avé
Patrick
P
Huerre
Michel
M
Gicquel
Brigitte
B
Jackson
Mary
M
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
D008055:Lipids; D026361:Reactive Nitrogen Species; C008901:phthiocerol dimycocerosate