Pathogenic mycobacterium upregulates cholesterol 25-hydroxylase to promote granuloma development via foam cell formation
Shuang Zhou, Ding Zhang, Dan Li, Hankun Wang, Cairong Ding, Jingrui Song, Wei-Feng Huang, Xuan Xia, Ziwei Zhou, Shanshan Han, Zhu Jin, Bo Yan, Jacqueline Gonzales, Laura E. Via, Lu Zhang, Decheng Wang
Abstract
Pathogenic mycobacteria orchestrate the complex cell populations known as granuloma that is the hallmark of tuberculosis. Foam cells, a lipid-rich cell-type, are considered critical for granuloma formation; however, the causative factor in foam cell formation remains unclear. Atherosclerosis is a chronic inflammatory disease characterized by the abundant accumulation of lipid-laden-macrophage-derived foam cells during which cholesterol 25-hydroxylase (CH25H) is crucial in foam cell formation. Here, we show that M . marinum ( Mm ), a relative of M . tuberculosis , induces foam cell formation, leading to granuloma development following CH25H upregulation. Moreover, the Mm -driven increase in CH25H expression is associated with the presence of phthiocerol dimycocerosate, a determinant for Mm virulence and integrity. CH25H- null mice showed decreased foam cell formation and attenuated pathology. Atorvastatin, a recommended first-line lipid-lowering drug, promoted the elimination of M. marinum and concomitantly reduced CH25H production. These results define a previously unknown role for CH25H in controlling macrophage-derived foam cell formation and Tuberculosis pathology.