Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine.

Autor: Peng, Cheng, Cheng, Yuanna, Ma, Mingtong, Chen, Qiu, Duan, Yongjia, Liu, Shanshan, Cheng, Hongyu, Yang, Hua, Huang, Jingping, Bu, Wenyi, Shi, Chenyue, Wu, Xiangyang, Chen, Jianxia, Zheng, Ruijuan, Liu, Zhonghua, Ji, Zhe, Wang, Jie, Huang, Xiaochen, Wang, Peng, Sha, Wei
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Zdroj: Nature Communications; 5/17/2024, Vol. 15 Issue 1, p1-19, 19p
Abstrakt: 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. In this work, authors mechanistically investigate the reduced induction of antimicrobial peptides in Mycobacterium tuberculosis infected macrophages. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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