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.
PMID: 33987949 DOI: 10.15252/embr.202051678
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.
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