161944.2-20230313195700-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf (16.79 MB)
A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages.
journal contributionposted on 2023-03-22, 11:07 authored by Melissa Bedard, Sanne van der Niet, Elliott M 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 G 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.
Crick (Grant ID: 10092, Grant title: Gutierrez FC001092)