Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection PMID: 33987949

ADC Targets in Oncology

2026-04-10

Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection

EMBO Rep. 2021 Jul 5;22(7):e51678. doi: 10.15252/embr.202051678.

Xiangyang Wu ¹ , Yong Wu ² , Ruijuan Zheng ¹ , Fen Tang ¹ , Lianhua Qin ¹ , Detian Lai ¹ , Lu Zhang ³ , Lingming Chen ⁴ , Bo Yan ⁵ , Hua Yang ¹ , Yang Wang ¹ , Feifei Li ² , Jinyu Zhang ³ , Fei Wang ¹ , Lin Wang ¹ , Yajuan Cao ¹ , Mingtong Ma ¹ , Zhonghua Liu ¹ , Jianxia Chen ¹ , Xiaochen Huang ¹ , Jie Wang ¹ , Ruiliang Jin ¹ , Peng Wang ⁶ , Qin Sun ⁶ , Wei Sha ⁶ , Liangdong Lyu ⁷ , Pedro Moura-Alves ⁸ ⁹ , Anca Dorhoi ⁸ ¹⁰ , Gang Pei ⁸ , Peng Zhang ¹¹ , Jiayu Chen ¹² , Shaorong Gao ¹² , Felix Randow ¹³ , Gucheng Zeng ⁴ , Chang Chen ¹¹ , Xin-Shan Ye ² , Stefan H E Kaufmann ⁸ ¹⁴ ¹⁵ , Haipeng Liu ¹ ⁸ ¹⁶ ¹⁷ , Baoxue Ge ¹ ¹⁶

Affiliations

1. Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
2. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
3. State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai, China.
4. Department of Microbiology, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
5. Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
6. Department of TB, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
7. Key Laboratory of Medical Molecular Virology of the Ministry of Education/Ministry of Health, School of Basic Medical Sciences, Fudan University, Shanghai, China.
8. Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
9. Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
10. Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany.
11. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
12. Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
13. Division of Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, UK.
14. Hagler Institute for Advanced Study at Texas A&M University, College Station, TX, USA.
15. Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
16. Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
17. Central Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.

Abstract

Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio-synthetical target for anti-tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by Galectin-9 and exacerbates mycobacterial Infection. Administration of AG-specific Aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb-infected mice or Mycobacterium marinum-infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of Galectin-9 with high affinity, and Galectin-9 associates with transforming growth factor β-activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal-regulated kinase (ERK) as well as induction of the expression of Matrix Metalloproteinases (MMPs). Moreover, deletion of Galectin-9 or inhibition of MMPs blocks AG-induced pathological impairments in the lung, and the AG-galectin-9 axis aggravates the process of Mtb Infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and Galectin-9 is a novel receptor for Mtb and Other mycobacteria, paving the way for the development of novel effective TB immune modulators.

Keywords

galectin-9; matrix metalloproteinases; mycobacterial arabinogalactan; transforming growth factor β-activated kinase 1; virulence factor.