Enhanced Autophagy and Cholesterol Efflux in Mouse Mesenchymal Stem Cells Infected with H37Rv Compared to H37Ra

Heng Li; Yan Yin; Wei Cao; Shichao Chen; Jianxia Chen; Yanchun Xing; Hong Yang

doi:10.1016/j.micpath.2024.107199

Enhanced Autophagy and Cholesterol Efflux in Mouse Mesenchymal Stem Cells Infected with H37Rv Compared to H37Ra

Microb Pathog. 2024 Dec 7:107199. doi: 10.1016/j.micpath.2024.107199. Online ahead of print.

Authors

Heng Li¹, Yan Yin², Wei Cao³, Shichao Chen⁴, Jianxia Chen⁵, Yanchun Xing⁶, Hong Yang⁷

Affiliations

¹ College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
² Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.
³ Institute of health, Shanghai Institute of life sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁴ College of Life Science and Technology, Tongji University, Shanghai 200092, China.
⁵ Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai TB Key Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; TB Department, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
⁶ Department of Medicine, Anhui Huangshan Vocational and Technical College, Huangshan, Anhui, 245000, China. Electronic address: Yanchun_Xing@163.com.
⁷ Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Shanghai TB Key Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China; Department of Medicine, Anhui Huangshan Vocational and Technical College, Huangshan, Anhui, 245000, China; Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai 200092, China. Electronic address: hyang@tongji.edu.cn.

PMID: 39653283
DOI: 10.1016/j.micpath.2024.107199

Abstract

Autophagy, metabolism, and associated signaling pathways play critical roles in bacterial survival within mammalian cells and influence the immunopathogenesis of infections. Mesenchymal stem cells (MSCs) are important host cells during Mycobacterium tuberculosis (Mtb) infection, yet how autophagy, metabolism, and related pathways are modulated in MSCs infected with the virulent H37Rv or the attenuated H37Ra strain of Mtb remains poorly understood. In this study, we utilized RNA-Seq screening, qRT-PCR, and Western Blotting to investigate the differences in these processes between H37Rv and H37Ra infections. Our results show that, at early time points (no more than 24h), infection with H37Rv significantly increased the expression of TlLR2, Prkaa2, and Prkaa2 phosphorylation in MSCs compared with H37Ra infection. Further analysis revealed that H37Rv infection induced a stronger autophagic response (evidenced by increased Atg9b and LC3II/LC3I) through the TLR2-AMP-AMPK pathway than H37Ra infection. Despite these differences in autophagy, there was no statistically significant difference in bacillary loads, suggesting that, in addition to autophagy, other factors such as apoptosis and immune-inflammatory responses may also regulate Mtb growth in MSCs. Additionally, the metabolic analysis showed that H37Rv infection led to increased expression of SLC2A3, PFKFB3, HK1, and ABCA1 in MSCs compared to H37Ra infection. These findings confirm that, during the early stages of infection, H37Rv induces enhanced autophagy, glucose metabolism, and cholesterol efflux through a more active TLR2-AMP-AMPK pathway than H37Ra. Therefore, MSCs may represent a novel target for the prevention and treatment of tuberculosis.

Keywords: H37Ra; H37Rv; autophagy; mesenchymal stem cell; metabolism; tuberculosis.