A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages

Melissa Bedard, Sanne van der Niet, Elliott Bernard, Gregory Babunovic, Tan-Yun Cheng, Beren Aylan, Anita Grootemaat, Sahadevan Raman, Laure Botella, Eri Ishikawa, Mary O'Sullivan, Seómadh O'Leary, Jacob Mayfield, Jeffrey Buter, Adriaan Minnaard, Sarah Fortune, Leon O'Murphy, Daniel Ory, Joseph Keane, Sho YamazakiMaximiliano Gutierrez, Nicole van der Wel, Branch Moody

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Number of pages18
JournalJournal of Clinical Investigation
Issue number6
Publication statusPublished - 9 Feb 2023
Externally publishedYes


  • immunology
  • tuberculosis
  • autophagy


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