2. Academic Validation
  3. Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine

Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine

  • Nat Commun. 2024 May 17;15(1):4216. doi: 10.1038/s41467-024-48588-4.
Cheng Peng # 1 2,  Yuanna Cheng # 1 2,  Mingtong Ma # 1 2,  Qiu Chen 1 2,  Yongjia Duan 1 2,  Shanshan Liu 1 2,  Hongyu Cheng 1 2,  Hua Yang 1 3,  Jingping Huang 1 2,  Wenyi Bu 1 2,  Chenyue Shi 1 2,  Xiangyang Wu 1 4,  Jianxia Chen 1 3 4,  Ruijuan Zheng 1 3,  Zhonghua Liu 1 3,  Zhe Ji 2,  Jie Wang 1 3,  Xiaochen Huang 1 3,  Peng Wang 3,  Wei Sha 3,  Baoxue Ge 5 6 7 8,  Lin Wang 9 10 11
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China.
  • 3 Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 4 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 5 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. gebaoxue@sibs.ac.cn.
  • 6 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China. gebaoxue@sibs.ac.cn.
  • 7 Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. gebaoxue@sibs.ac.cn.
  • 8 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. gebaoxue@sibs.ac.cn.
  • 9 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. 651377481@qq.com.
  • 10 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China. 651377481@qq.com.
  • 11 Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. 651377481@qq.com.
  • # Contributed equally.
PMID: 38760394 DOI: 10.1038/s41467-024-48588-4
Abstract

Antimicrobial Peptides (AMPs), ancient scavengers of bacteria, are very poorly induced in macrophages infected by Mycobacterium tuberculosis (M. tuberculosis), but the underlying mechanism remains unknown. Here, we report that L-alanine interacts with PRSS1 and unfreezes the inhibitory effect of PRSS1 on the activation of NF-κB pathway to induce the expression of AMPs, but mycobacterial alanine dehydrogenase (Ald) Rv2780 hydrolyzes L-alanine and reduces the level of L-alanine in macrophages, thereby suppressing the expression of AMPs to facilitate survival of mycobacteria. Mechanistically, PRSS1 associates with TAK1 and disruptes the formation of TAK1/TAB1 complex to inhibit TAK1-mediated activation of NF-κB pathway, but interaction of L-alanine with PRSS1, disables PRSS1-mediated impairment on TAK1/TAB1 complex formation, thereby triggering the activation of NF-κB pathway to induce expression of AMPs. Moreover, deletion of antimicrobial peptide gene β-defensin 4 (Defb4) impairs the virulence by Rv2780 during Infection in mice. Both L-alanine and the Rv2780 inhibitor, GWP-042, exhibits excellent inhibitory activity against M. tuberculosis Infection in vivo. Our findings identify a previously unrecognized mechanism that M. tuberculosis uses its own alanine dehydrogenase to suppress host immunity, and provide insights relevant to the development of effective immunomodulators that target M. tuberculosis.

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