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

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. [email protected].
6 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China. [email protected].
7 Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
8 Clinical Translation Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
9 Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
10 Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China. [email protected].
11 Shanghai Clinic and Research Center of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China. [email protected].
# 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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-45854

GWP-042

Antimicrobial Agent

Bacterial

Infection

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