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Bedard, Melissa; van der Niet, Sanne; Bernard, Elliott M; Babunovic, Gregory; Cheng, Tan-Yun; Aylan, Beren; Grootemaat, Anita E; Raman, Sahadevan; Botella, Laure; Ishikawa, Eri; O'Sullivan, Mary P; O'Leary, Seónadh; Mayfield, Jacob A; Buter, Jeffrey; Minnaard, Adriaan J; Fortune, Sarah M; Murphy, Leon O; Ory, Daniel S; Keane, Joseph; Yamasaki, Sho; Gutierrez, Maximiliano G; van der Wel, Nicole; Moody, D Branch
The Journal of clinical investigation, 03/2023, Letnik: 133, Številka: 6Journal Article
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.
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in: SICRIS
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