A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages
Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-03-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI161944 |
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| author | Melissa Bedard Sanne van der Niet Elliott M. Bernard Gregory Babunovic Tan-Yun Cheng Beren Aylan Anita E. Grootemaat Sahadevan Raman Laure Botella Eri Ishikawa Mary P. O’Sullivan Seónadh O’Leary Jacob A. Mayfield Jeffrey Buter Adriaan J. Minnaard Sarah M. Fortune Leon O. Murphy Daniel S. Ory Joseph Keane Sho Yamasaki Maximiliano G. Gutierrez Nicole van der Wel D. Branch Moody |
| author_facet | Melissa Bedard Sanne van der Niet Elliott M. Bernard Gregory Babunovic Tan-Yun Cheng Beren Aylan Anita E. Grootemaat Sahadevan Raman Laure Botella Eri Ishikawa Mary P. O’Sullivan Seónadh O’Leary Jacob A. Mayfield Jeffrey Buter Adriaan J. Minnaard Sarah M. Fortune Leon O. Murphy Daniel S. Ory Joseph Keane Sho Yamasaki Maximiliano G. Gutierrez Nicole van der Wel D. Branch Moody |
| author_sort | Melissa Bedard |
| collection | DOAJ |
| description | Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside–producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd–induced lipid substrates that define Gaucher’s disease, Wolman’s disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis–induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages. |
| first_indexed | 2024-03-11T12:08:48Z |
| format | Article |
| id | doaj.art-66ad604010504fdab74173379c2c7ca6 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:48Z |
| publishDate | 2023-03-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-66ad604010504fdab74173379c2c7ca62023-11-07T16:20:04ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-03-011336A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophagesMelissa BedardSanne van der NietElliott M. BernardGregory BabunovicTan-Yun ChengBeren AylanAnita E. GrootemaatSahadevan RamanLaure BotellaEri IshikawaMary P. O’SullivanSeónadh O’LearyJacob A. MayfieldJeffrey ButerAdriaan J. MinnaardSarah M. FortuneLeon O. MurphyDaniel S. OryJoseph KeaneSho YamasakiMaximiliano G. GutierrezNicole van der WelD. Branch MoodyInduction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves the transformation of infected phagolysosomes from a site of killing into a nutrient-rich replicative niche. Here, we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), caused lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside–producing M. tuberculosis, caused intralysosomal and peribacillary lipid storage patterns that matched both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters and that 1-TbAd increased M. tuberculosis growth under conditions of restricted lipid access in macrophages. Furthermore, lipidomics identified 1-TbAd–induced lipid substrates that define Gaucher’s disease, Wolman’s disease, and other inborn lysosomal storage diseases. These data identify genetic and molecular causes of M. tuberculosis–induced lysosomal failure, leading to successful testing of an agonist of TRPML1 calcium channels that reverses lipid storage in cells. These data establish the host-directed cellular functions of an orphan effector molecule that promotes survival in macrophages, providing both an upstream cause and detailed picture of lysosome failure in foamy macrophages.https://doi.org/10.1172/JCI161944Infectious diseaseMicrobiology |
| spellingShingle | Melissa Bedard Sanne van der Niet Elliott M. Bernard Gregory Babunovic Tan-Yun Cheng Beren Aylan Anita E. Grootemaat Sahadevan Raman Laure Botella Eri Ishikawa Mary P. O’Sullivan Seónadh O’Leary Jacob A. Mayfield Jeffrey Buter Adriaan J. Minnaard Sarah M. Fortune Leon O. Murphy Daniel S. Ory Joseph Keane Sho Yamasaki Maximiliano G. Gutierrez Nicole van der Wel D. Branch Moody A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages The Journal of Clinical Investigation Infectious disease Microbiology |
| title | A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages |
| title_full | A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages |
| title_fullStr | A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages |
| title_full_unstemmed | A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages |
| title_short | A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages |
| title_sort | terpene nucleoside from m tuberculosis induces lysosomal lipid storage in foamy macrophages |
| topic | Infectious disease Microbiology |
| url | https://doi.org/10.1172/JCI161944 |
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