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

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Induction of lipid-laden foamy macrophages is a cellular hallmark of tuberculosis (TB) disease, which involves transformation of infected phagolysomes from a site of killing into a nutrient-rich replicative niche. Here we show that a terpenyl nucleoside shed from Mycobacterium tuberculosis (Mtb), 1-tuberculosinyladenosine (1-TbAd), causes lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages. Pure 1-TbAd, or infection with terpenyl nucleoside-producing Mtb, caused intralysosomal and peribacillary lipid storage patterns that match both the molecules and subcellular locations known in foamy macrophages. Lipidomics showed that 1-TbAd induced storage of triacylglycerides and cholesterylesters, and 1-TbAd increased Mtb growth under conditions of restricted lipid access in macrophages. Further, lipidomics dentified 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 Mtb-induced lysosomal failure, leading to successful testing of an gonist 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.

Journal details

Volume 133
Issue number 6
Pages e161944
Available online
Publication date