Phthiocerol Dimycocerosates of M. tuberculosis Participate in Macrophage Invasion by Inducing Changes in the Organization of Plasma Membrane Lipids

PLoS Pathogens

Wladimir Malaga¹  Christian Chalut¹  Christophe Guilhot¹  Catherine Astarie-Dequeker¹  Laurent Le Guyader²  Fam-Ky Seaphanh²  André Lopez² 

[1] CNRS, Institut de Pharmacologie et de Biologie Structurale (IPBS), Toulouse, France;Université de Toulouse, UPS, IPBS, Toulouse, France

关键词: Mycobacterium tuberculosis;    Macrophages;    Cell membranes;    Phagocytosis;    Phagosomes;    Lipids;    Cholesterol;    Mycobacterium bovis;   

DOI  :  10.1371/journal.ppat.1000289

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY