Mycobacterium tuberculosis releases an antacid that remodels phagosomes

Jeffrey Buter; Tan-Yun Cheng; Marwan Ghanem; Anita E Grootemaat; Sahadevan Raman; Xinxin Feng; Ashmir R Plantijn; Thomas Ennis; Joyce Wang; Rachel N Cotton; Emilie Layre; Alexandrea K Ramnarine; Jacob A Mayfield; David C Young; Amanda Jezek Martinot; Noman Siddiqi; Shoko Wakabayashi; Helene Botella; Roger Calderon; Megan Murray; Sabine Ehrt; Barry B Snider; Michael B Reed; Eric Oldfield; Shumin Tan; Eric J Rubin; Marcel A Behr; Nicole N van der Wel; Adriaan J Minnaard; D Branch Moody

doi:10.1038/s41589-019-0336-0

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Mycobacterium tuberculosis releases an antacid that remodels phagosomes

Journal article

Open access

Peer reviewed

Mycobacterium tuberculosis releases an antacid that remodels phagosomes

Jeffrey Buter, Tan-Yun Cheng, Marwan Ghanem, Anita E Grootemaat, Sahadevan Raman, Xinxin Feng, Ashmir R Plantijn, Thomas Ennis, Joyce Wang, Rachel N Cotton, …

Nature chemical biology, Vol.15(9), pp.889-899

09/2019

DOI: https://doi.org/10.1038/s41589-019-0336-0

PMID: 31427817

Abstract

Prevalence

Humans

Phagosomes - metabolism

Lysosomes

Lipids - biosynthesis

Antacids - metabolism

Lipids - chemistry

Macrophages - metabolism

Animals

Mycobacterium kansasii - genetics

Mice

Molecular Structure

Gene Expression Regulation, Bacterial

Mycobacterium tuberculosis - metabolism

Hydrogen-Ion Concentration

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.

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

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Title: Mycobacterium tuberculosis releases an antacid that remodels phagosomes
Creators: Jeffrey Buter - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Tan-Yun Cheng - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Marwan Ghanem - Infectious Diseases and Immunity in Global Health, McGill University Health Centre Research Institute, McGill International TB Centre, Montreal, Canada
Anita E Grootemaat - Electron Microscopy Center Amsterdam, Department of Medical Biology, Amsterdam UMC, Amsterdam, the Netherlands
Sahadevan Raman - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Xinxin Feng - Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
Ashmir R Plantijn - Stratingh Institute for Chemistry, University of Groningen, Groningen, the Netherlands
Thomas Ennis - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Joyce Wang - Infectious Diseases and Immunity in Global Health, McGill University Health Centre Research Institute, McGill International TB Centre, Montreal, Canada
Rachel N Cotton - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Emilie Layre - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Alexandrea K Ramnarine - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Jacob A Mayfield - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
David C Young - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Amanda Jezek Martinot - Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA
Noman Siddiqi - Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA
Shoko Wakabayashi - Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA
Helene Botella - Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA
Roger Calderon - Socios en Salud Sucursal Peru, Lima, Peru
Megan Murray - Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA
Sabine Ehrt - Department of Microbiology and Immunology, Weill Cornell Medical College, New York, NY, USA
Barry B Snider - Department of Chemistry, Brandeis University, Waltham, MA, USA
Michael B Reed - Infectious Diseases and Immunity in Global Health, McGill University Health Centre Research Institute, McGill International TB Centre, Montreal, Canada
Eric Oldfield - Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA
Shumin Tan - Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, USA
Eric J Rubin - Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA
Marcel A Behr - Infectious Diseases and Immunity in Global Health, McGill University Health Centre Research Institute, McGill International TB Centre, Montreal, Canada
Nicole N van der Wel - Electron Microscopy Center Amsterdam, Department of Medical Biology, Amsterdam UMC, Amsterdam, the Netherlands
Adriaan J Minnaard - Stratingh Institute for Chemistry, University of Groningen, Groningen, the Netherlands
D Branch Moody - Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. bmoody@bwh.harvard.edu
Publication Details: Nature chemical biology, Vol.15(9), pp.889-899
Grant note: R01 AI116604 / NIAID NIH HHS K08 AI135098 / NIAID NIH HHS U19 AI111224 / NIAID NIH HHS
Identifiers: 9924012824201921
Academic Unit: Department of Chemistry
Language: English
Resource Type: Journal article

Mycobacterium tuberculosis releases an antacid that remodels phagosomes

Abstract

UN Sustainable Development Goals (SDGs)

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