title: Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids.
abstract: Phthiocerol dimycocerosates (DIM) are major virulence factors of Mycobacterium tuberculosis (Mtb), in particular during the early step of infection when bacilli encounter their host macrophages. However, their cellular and molecular mechanisms of action remain unknown. Using Mtb mutants deleted for genes involved in DIM biosynthesis, we demonstrated that DIM participate both in the receptor-dependent phagocytosis of Mtb and the prevention of phagosomal acidification. The effects of DIM required a state of the membrane fluidity as demonstrated by experiments conducted with cholesterol-depleting drugs that abolished the differences in phagocytosis efficiency and phagosome acidification observed between wild-type and mutant strains. The insertion of a new cholesterol-pyrene probe in living cells demonstrated that the polarity of the membrane hydrophobic core changed upon contact with Mtb whereas the lateral diffusion of cholesterol was unaffected. This effect was dependent on DIM and was consistent with the effect observed following DIM insertion in model membrane. Therefore, we propose that DIM control the invasion of macrophages by Mtb by targeting lipid organisation in the host membrane, thereby modifying its biophysical properties. The DIM-induced changes in lipid ordering favour the efficiency of receptor-mediated phagocytosis of Mtb and contribute to the control of phagosomal pH driving bacilli in a protective niche.
authors.affiliation: CNRS, Institut de Pharmacologie et de Biologie Structurale (IPBS), Toulouse, France. catherine.astarie-dequeker@ipbs.fr
authors.forename: Catherine
authors.initials: C
authors.lastname: Astarie-Dequeker
authors.forename: Laurent
authors.initials: L
authors.lastname: Le Guyader
authors.forename: Wladimir
authors.initials: W
authors.lastname: Malaga
authors.forename: Fam-Ky
authors.initials: FK
authors.lastname: Seaphanh
authors.forename: Christian
authors.initials: C
authors.lastname: Chalut
authors.forename: André
authors.initials: A
authors.lastname: Lopez
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilhot
mesh_terms: D002462:Cell Membrane / Q000378:metabolism* / Q000382:microbiology; D002784:Cholesterol / Q000378:metabolism; D055786:Gene Knockout Techniques; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008027:Light; D008055:Lipids / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000378:metabolism* / Q000382:microbiology; D008563:Membrane Lipids / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D010587:Phagocytosis; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology; D012542:Scattering, Radiation; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D008055:Lipids; D008563:Membrane Lipids; D037521:Virulence Factors; C008901:phthiocerol dimycocerosate; D002784:Cholesterol