Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection.

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.

• Authors: 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
• Journal: EMBO reports (EMBO Rep) Vol. 22 Issue 7 Pg. e51678 (07 05 2021) ISSN: 1469-3178 [Electronic] England
• PMID: 33987949 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors.

Chemical References

• Galactans
• Galectins
• galectin 9, mouse
• arabinogalactan

Topics

• Animals
• Galactans
• Galectins (genetics)
• Mice
• Mycobacterium tuberculosis
• Zebrafish