A terpenyl nucleoside from Mycobacterium tuberculosis, 1-tuberculosinyladenosine (1-TbAd), may be responsible for extensive M1 macrophages lipid accumulation that resembles the pathological substrate found in lysosomal storage diseases like lysosomal acid lipase deficiency (LAL-D) and Gaucher’s disease, according to an article recently published in The Journal of Clinical Investigation.
For the study, the authors analyzed human and mouse macrophage cells. They used CD14+ monocytes differentiated into M1 and M2 macrophages and human alveolar macrophages retrieved by bronchial washes as well as RAW264 macrophages and murine bone marrow macrophages originating from mice.
The cells were observed under a microscope and subjected to luminescence measurement and CFU enumeration, immunological assays, immunofluorescence labeling of infected macrophages, enzyme bioactivity assays, western blotting, and HPLC-MS analysis of mammalian lipid extracts.
According to the results, 1-TbAd may cause “lysosomal maturation arrest and autophagy blockade, leading to lipid storage in M1 macrophages.” Pure 1-TbAd, or infection with terpenyl nucleoside-producing M tuberculosis, may trigger intralysosomal and peribacillary lipid storage patterns found in foamy macrophages.
The bacterial nucleoside may selectively induce the accumulation of neutral lipids including triacylglycerides and cholesteryl esters, as well as enhance the growth of M tuberculosis under conditions of restricted lipid access.
The lipidomics analysis also revealed the presence of lipid substrates that define Wolman disease, a severe form of LAL-D with infant onset, as well as Gaucher’s disease and other inborn lysosomal storage diseases.
“1-TbAd does not alter transcription of key enzymes, and it would not be expected to interact with the active site of diverse enzymes that process lipid and peptide substrates,” Bedard and colleagues wrote.
Read more about LAL-D etiology
As they identified the underlying genetic and molecular factors behind M tuberculosis-induced lysosomal failure, the study authors tested if 1-TbAd lysosomal dysfunction could be pharmacologically reversed. They treated macrophages with C8, a selective agonist of the transient receptor potential mucolipin 1, resulting in a complete reversal of the excessive cellular lipid storage.
“These data provide a potential point of entry for host-focused ‘lysosomal’ therapy since key effects of 1-TbAd on human macrophages can be largely prevented by a drug that acts on upstream control pathways to broadly restore lysosomal homeostasis,” they added.
The creation of foamy macrophages represents a key pathological hallmark of natural tuberculosis disease.
Bedard M, van der Niet S, Bernard EM, et al. A terpene nucleoside from M. tuberculosis induces lysosomal lipid storage in foamy macrophages. J Clin Invest. Published online February 9, 2023. doi:10.1172/JCI161944