Mechanism of Phagolysosome Biogenesis Block by Viable Mycobacterium tuberculosis

Live Mycobacterium tuberculosis persists in macrophage phagosomes by interfering with phagolysosome biogenesis. Here, using four-dimensional microscopy and in vitro assays, we report the principal difference between phagosomes containing live and dead mycobacteria. Phosphatidylinositol 3-phosphate (...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 11; pp. 4033 - 4038
Main Authors Vergne, Isabelle, Chua, Jennifer, Lee, Hwang-Ho, Lucas, Megan, Belisle, John, Deretic, Vojo, Collier, R. John
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 15.03.2005
National Acad Sciences
Subjects
Animals
Biological Sciences
Calcium - metabolism
Cellular biology
Endosomes
Fluorescence
Lipids
Macrophages
Macrophages - microbiology
Macrophages - physiology
Mice
Microscopy
Molybdates
Mycobacterium tuberculosis
Mycobacterium tuberculosis - pathogenicity
Mycobacterium tuberculosis - physiology
Phagosomes
Phagosomes - physiology
Phosphatases
Phosphatidylinositol 3-Kinases - metabolism
Phosphatidylinositol Phosphates - metabolism
Phosphatidylinositols
Scientific imaging
Tuberculosis
Online AccessGet full text

Cover

More Information
Summary:Live Mycobacterium tuberculosis persists in macrophage phagosomes by interfering with phagolysosome biogenesis. Here, using four-dimensional microscopy and in vitro assays, we report the principal difference between phagosomes containing live and dead mycobacteria. Phosphatidylinositol 3-phosphate (PI3P), a membrane trafficking regulatory lipid essential for phagosomal acquisition of lysosomal constituents, is retained on phagosomes harboring dead mycobacteria but is continuously eliminated from phagosomes with live bacilli. We show that the exclusion of PI3P from live mycobacterial phagosomes can be only transiently reversed by Ca2+fluxes, and that live M. tuberculosis secretes a lipid phosphatase, SapM, that hydrolyzes PI3P, inhibits phagosome-late endosome fusion in vitro, and contributes to inhibition of phagosomal maturation.
Bibliography:SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 14
ObjectType-Article-1
ObjectType-Feature-2
content type line 23
I.V. and J.C. contributed equally to this work.
To whom correspondence should be addressed. E-mail: vderetic@salud.unm.edu.
This paper was submitted directly (Track II) to the PNAS office.
Edited by R. John Collier, Harvard Medical School, Boston, MA, and approved January 26, 2005
Abbreviations: PI3K, phosphatidylinositol 3-kinase; PI3P, phosphatidylinositol 3-phosphate; 4D, four-dimensional; BCG, bacillus Calmette–Guérin; MtCFP, Mycobacterium tuberculosis H37Rv culture filtrate protein; RFU, relative fluorescence unit; MTM, myotubularin.
Author contributions: I.V., J.C., J.B., and V.D. designed research; I.V., J.C., and H.-H.L. performed research; I.V., J.C., M.L., and J.B. contributed new reagents/analytic tools; I.V., J.C., H.-H.L., and V.D. analyzed data; J.C. planned and performed UltraView 4D microscopy and analyzed live microscopy data with GFP probes; I.V. planned and carried out Ca2+ imaging studies; J.C. and I.V. generated figures; J.C. generated movies; and V.D. edited figures and finalized the text and the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0409716102