Nature Communications (May 2024)

Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine

  • Cheng Peng,
  • Yuanna Cheng,
  • Mingtong Ma,
  • Qiu Chen,
  • Yongjia Duan,
  • Shanshan Liu,
  • Hongyu Cheng,
  • Hua Yang,
  • Jingping Huang,
  • Wenyi Bu,
  • Chenyue Shi,
  • Xiangyang Wu,
  • Jianxia Chen,
  • Ruijuan Zheng,
  • Zhonghua Liu,
  • Zhe Ji,
  • Jie Wang,
  • Xiaochen Huang,
  • Peng Wang,
  • Wei Sha,
  • Baoxue Ge,
  • Lin Wang

DOI
https://doi.org/10.1038/s41467-024-48588-4
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 19

Abstract

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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.