Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection

Xiangyang Wu; Yong Wu; Ruijuan Zheng; Fen Tang; Lianhua Qin; Detian Lai; Lu Zhang; Lingming Chen; Bo Yan; Hua Yang; Yang Wang; Feifei Li; Jinyu Zhang; Fei Wang; Lin Wang; Yajuan Cao; Mingtong Ma; Zhonghua Liu; Jianxia Chen; Xiaochen Huang; Jie Wang; Ruiliang Jin; Peng Wang; Qin Sun; Wei Sha; Liangdong Lyu; Pedro Moura-Alves; Anca Dorhoi; Gang Pei; Peng Zhang; Jiayu Chen; Shaorong Gao; Felix Randow; Gucheng Zeng; Chang Chen; Xin-Shan Ye; Stefan H E Kaufmann; Haipeng Liu; Baoxue Ge

doi:10.15252/embr.202051678

Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection

EMBO Rep. 2021 Jul 5;22(7):e51678. doi: 10.15252/embr.202051678. Epub 2021 May 13.

Authors

Xiangyang Wu¹, Yong Wu², Ruijuan Zheng¹, Fen Tang¹, Lianhua Qin¹, Detian Lai¹, Lu Zhang³, Lingming Chen⁴, Bo Yan⁵, Hua Yang¹, Yang Wang¹, Feifei Li², Jinyu Zhang³, Fei Wang¹, Lin Wang¹, Yajuan Cao¹, Mingtong Ma¹, Zhonghua Liu¹, Jianxia Chen¹, Xiaochen Huang¹, Jie Wang¹, Ruiliang Jin¹, Peng Wang⁶, Qin Sun⁶, Wei Sha⁶, Liangdong Lyu⁷, Pedro Moura-Alves^{8

9}, Anca Dorhoi^{8

10}, Gang Pei⁸, Peng Zhang¹¹, Jiayu Chen¹², Shaorong Gao¹², Felix Randow¹³, Gucheng Zeng⁴, Chang Chen¹¹, Xin-Shan Ye², 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Galactans
Galectins / genetics
Mice
Mycobacterium tuberculosis*
Zebrafish*

Substances

Galactans
Galectins
galectin 9, mouse
arabinogalactan

Grants and funding

MC_U105170648/MRC_/Medical Research Council/United Kingdom