Mycobacterium tuberculosis inactivates host oxysterols to impair macrophage cholesterol homeostasis
Host oxysterols coordinate macrophage cholesterol homeostasis and antimicrobial defense, but whether pathogens directly target oxysterol signaling is unknown. Here, we identify pathogen-mediated enzymatic oxysterol inactivation as a mechanism by which Mycobacterium tuberculosis (Mtb) subverts host cholesterol metabolism. Mtb oxidizes the endogenous oxysterols 27-hydroxycholesterol (27-HC) and…
Mycobacterium tuberculosis (Mtb) hijacks host oxysterol signaling to manipulate macrophage cholesterol management, as demonstrated in a recent study. The pathogen generates enzymatic oxysterol inactivation, targeting the endogenous oxysterols 27-hydroxycholesterol (27-HC) and 3{beta}-hydroxycholest-5-enoic acid (3{beta}-HCA). This leads to the formation of new metabolites, 27-hydroxycholest-4-en-3-one (27-HCO) and 3-oxocholest-4-enoic acid (3O-CA), which accumulate in sputum lipidomics from TB patients across three continents during active disease.
Treatment reverts these metabolic signatures to normal levels. In human macrophages, Mtb 3{beta}-hydroxysteroid dehydrogenase (3{beta}-Hsd) converts 3{beta}-HCA to 27-HCO. Unlike the parent oxysterols, these new compounds do not activate liver X receptor (LXR) or suppress sterol regulatory element-binding protein 2 (SREBP2) target genes.
Consequently, Mtb's enzymatic oxysterol inactivation hinders macrophage cholesterol homeostasis, resulting in a phenotype where the bacteria can thrive. The restoration of this disrupted homeostasis occurs with LXR antagonism, highlighting the crucial role of Mtb's oxysterol inactivation in its pathogenicity.
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