A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophagesMore about Open Access at the Crick
Authors listMelissa Bedard Sanne van der Niet Elliott 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 Gutierrez Nicole van der Wel D Branch Moody
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.
Issue number 6