2. Academic Validation
  3. Mycobacterium tuberculosis Suppresses Inflammatory Responses in Host through Its Cholesterol Metabolites

Mycobacterium tuberculosis Suppresses Inflammatory Responses in Host through Its Cholesterol Metabolites

  • ACS Infect Dis. 2024 Oct 11;10(10):3650-3663. doi: 10.1021/acsinfecdis.4c00529.
Jing Wu 1,  Yong Zhang 1,  Wenqi Li 2,  Hao Tang 1,  Ying Zhou 3,  Di You 3,  Xiaohe Chu 1,  Hanbing Li 1,  Jinsai Shang 2,  Nan Qi 2 4,  Bang-Ce Ye 1 3
Affiliations

Affiliations

  • 1 Institute of Engineering Biology and Health, Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, China.
  • 2 Department of Basic Research, Guangzhou National Laboratory, No. 9 XingDaoHuanBei Road, Guangzhou International Bio Island, Guangzhou 510005, Guangdong Province, China.
  • 3 Lab of Biosystems and Microanalysis, State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China.
  • 4 State Key Laboratory of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, Guangdong, China.
PMID: 39360613 DOI: 10.1021/acsinfecdis.4c00529
Abstract

Cholesterol is a key carbon source for Mycobacterium tuberculosis (Mtb) survival and persistence within macrophages. However, little is known about the role of Cholesterol metabolism by Mtb in host-Mtb interplay. Here, we report the immune suppression mediated by Mtb's Cholesterol metabolites. Conducting the Cholesterol metabolic profiling and loss-of-function experiments, we show that the Cholesterol oxidation products catalyzed by a thiolase FadA5 from Mtb H37Ra, 4-androstenedione (AD), and its derivant 1,4-androstenedione (ADD) inhibit the expression of pro-inflammatory cytokines and thus promote Bacterial survival in bone marrow-derived macrophages (BMDMs). Our time-resolved fluorescence resonance energy transfer (TR-FRET)-based screening further identifies the nuclear receptor LXRα as the target of ADD. Activation of LXRα via ADD impedes the nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPK) signaling and reduces Cholesterol accumulation in lipid rafts upon TLR4 simulation, thereby compromising the inflammatory responses. Our findings provide the evidence that Mtb could suppress the host immunity through its Cholesterol metabolic Enzyme and products, which are potential targets for screening novel anti-tuberculosis (TB) agents.

Keywords

LXRα; Mycobacterium tuberculosis; TLR4 signaling; cholesterol metabolism; inflammatory responses.

Figures
Products