TY - JOUR
T1 - Mycobacterium tuberculosis releases an antacid that remodels phagosomes
AU - Buter, Jeffrey
AU - Cheng, Tan Yun
AU - Ghanem, Marwan
AU - Grootemaat, Anita E.
AU - Raman, Sahadevan
AU - Feng, Xinxin
AU - Plantijn, Ashmir R.
AU - Ennis, Thomas
AU - Wang, Joyce
AU - Cotton, Rachel N.
AU - Layre, Emilie
AU - Ramnarine, Alexandrea K.
AU - Mayfield, Jacob A.
AU - Young, David C.
AU - Jezek Martinot, Amanda
AU - Siddiqi, Noman
AU - Wakabayashi, Shoko
AU - Botella, Helene
AU - Calderon, Roger
AU - Murray, Megan
AU - Ehrt, Sabine
AU - Snider, Barry B.
AU - Reed, Michael B.
AU - Oldfield, Eric
AU - Tan, Shumin
AU - Rubin, Eric J.
AU - Behr, Marcel A.
AU - van der Wel, Nicole N.
AU - Minnaard, Adriaan J.
AU - Moody, D. Branch
N1 - The authors thank H. van Veen and W. Tigchelaar for EM, P. Reinink for phylogenetic graphs and S. Suliman for advice. Work was supported by grant nos. AI116604 (to D.B.M. and N.N.v.d.W.), AI111224 (to D.B.M. and M.M.), GM065307 (to E.O.), CA158191 (to E.O.) and AI114952 (to S.T.), the Dutch Science Foundation NWO-VICI 70.57.443 (to A.J.M.) and a Canadian Institute of Health Research Foundation grant 148362 (to M.A.B.).
PY - 2019/9/1
Y1 - 2019/9/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41589-019-0336-0
DO - 10.1038/s41589-019-0336-0
M3 - Article
C2 - 31427817
AN - SCOPUS:85070800866
SN - 1552-4450
VL - 15
SP - 889
EP - 899
JO - Nature chemical biology
JF - Nature chemical biology
IS - 9
ER -