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; Weifeng Huang; Xuan Xia; Ziwei Zhou; Shanshan Han; Zhu Jin; Bo Yan; Jacqueline Gonzales; Laura E Via; Lu Zhang; Decheng Wang

doi:10.1016/j.isci.2024.109204

Pathogenic mycobacterium upregulates cholesterol 25-hydroxylase to promote granuloma development via foam cell formation

iScience. 2024 Feb 12;27(3):109204. doi: 10.1016/j.isci.2024.109204. eCollection 2024 Mar 15.

Authors

Shuang Zhou¹, Ding Zhang¹, Dan Li², Hankun Wang¹, Cairong Ding¹, Jingrui Song¹, Weifeng Huang¹, Xuan Xia¹, Ziwei Zhou³, Shanshan Han¹, Zhu Jin², Bo Yan⁴, Jacqueline Gonzales⁵, Laura E Via^{5

6}, Lu Zhang³, Decheng Wang¹

Affiliations

¹ Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, China Three Gorges University; Institute of Infection and Inflammation, China Three Gorges University; College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, P.R. China.
² Department of Tuberculosis, The Third People's Hospital of Yichang, Yichang 443003, P.R. China.
³ State Key Laboratory of Genetic Engineering, Institute of Genetics, MOE Engineering Research Center of Gene Technology, School of Life Science, Fudan University, Shanghai 200433, P.R. China.
⁴ Shanghai Public Health Clinical Center, Fudan University, Shanghai China.
⁵ Tuberculosis Research Section, Laboratory of Clinical Infectious Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20982, USA.
⁶ Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.

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.

Keywords: Cell biology; Microbiology.