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

Abstract

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 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 Mtb-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.

The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids

“…In addition, immunofluorescence microscopy revealed a substantial induction of lipid inclusions (indicated by Nile red staining) at day four after infection with wild-type and complemented bacteria, compared with the 1-TbAd-deficient mutant. Lipid inclusions in M. tuberculosis-infected macrophages were clearly localized to phagolysosomal (i.e., LAMP1 + ) compartments, as revealed by CLEM (16).…”

“…Bedard et al (16) demonstrate that 1-TbAd produced by M. tuberculosis caused lysosomal failure and accumulation of lipids in macrophages, mimicking lysosomal storage diseases. Furthermore, their data suggest that M. tuberculosis used lipids stored in lysosomes to support its growth inside macrophages, especially under conditions of limited lipid access.…”

“…On the basis of these results, Bedard et al (16) hypothesized that by raising lysosomal pH, 1-TbAd inhibits the activity of intralysosomal acid hydrolases, resulting in the accumulation of lipids in this compartment. To address this hypothesis, the authors used enzyme-activated fluorogenic probes and showed that 1-TbAd strongly inhibited the acid-dependent glycosidase and protease activity within intact mac- dent lipid accumulation could be counteracted by the use of a drug that restores lysosomal function.…”

“…In this issue of the JCI, Bedard et al (16) shine a light on these processes. By using correlative light and electron microscopy (CLEM), Bedard et Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects primarily macrophages, causing them to differentiate into lipidladen foamy macrophages that are a primary source of tissue destruction in patients with TB.…”

“…Finally, Bedard et al sought to assess whether the lysosomal failure of macrophages triggered by 1-TbAd could be reversed using pharmacological regulators of lysosomal activity. In particular, they focused on an agonist (C8) of transient receptor potential mucolipin channel 1 (TRPML1), a lysosomal Ca 2+ release channel that prevents lysosomal dyshomeostasis (16)(17)(18)(19)(20). As hypothesized, of 1-TbAd-stimulated macrophages with C8 decreased the size of swollen lysosomes by more than twofold, dramatically reduced the number of lipid inclusions, and restored glycolipid catabolism (16).…”