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Nat Chem Biol. 2019 Sep;15(9):889-899. doi: 10.1038/s41589-019-0336-0. Epub 2019 Aug 19.

Mycobacterium tuberculosis releases an antacid that remodels phagosomes.

Author information

1
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
2
Infectious Diseases and Immunity in Global Health, McGill University Health Centre Research Institute, McGill International TB Centre, Montreal, Canada.
3
Electron Microscopy Center Amsterdam, Department of Medical Biology, Amsterdam UMC, Amsterdam, the Netherlands.
4
Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
5
Stratingh Institute for Chemistry, University of Groningen, Groningen, the Netherlands.
6
Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
7
Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA.
8
Socios en Salud Sucursal Peru, Lima, Peru.
9
Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
10
Department of Chemistry, Brandeis University, Waltham, MA, USA.
11
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA.
12
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. bmoody@bwh.harvard.edu.

Abstract

Mycobacterium tuberculosis (Mtb) is the world's most deadly pathogen. Unlike less virulent mycobacteria, Mtb produces 1-tuberculosinyladenosine (1-TbAd), an unusual terpene nucleoside of unknown function. In the present study 1-TbAd has been shown to be a naturally evolved phagolysosome disruptor. 1-TbAd is highly prevalent among patient-derived Mtb strains, where it is among the most abundant lipids produced. Synthesis of TbAd analogs and their testing in cells demonstrate that their biological action is dependent on lipid linkage to the 1-position of adenosine, which creates a strong conjugate base. Furthermore, C20 lipid moieties confer passage through membranes. 1-TbAd selectively accumulates in acidic compartments, where it neutralizes the pH and swells lysosomes, obliterating their multilamellar structure. During macrophage infection, a 1-TbAd biosynthesis gene (Rv3378c) confers marked phagosomal swelling and intraphagosomal inclusions, demonstrating an essential role in regulating the Mtb cellular microenvironment. Although macrophages kill intracellular bacteria through phagosome acidification, Mtb coats itself abundantly with antacid.

PMID:
31427817
DOI:
10.1038/s41589-019-0336-0
[Indexed for MEDLINE]

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