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.

抗菌肽（AMP）是古老的细菌清道夫，在结核分枝杆菌（M. tuberculosis）感染的巨噬细胞中的诱导效果非常差，但其潜在机制仍不清楚。在这里，我们报道L-丙氨酸与PRSS1相互作用并解冻PRSS1对NF-κB通路激活的抑制作用从而诱导AMP的表达，但分枝杆菌丙氨酸脱氢酶（Ald）Rv2780水解L-丙氨酸并降低AMPs的水平巨噬细胞中的L-丙氨酸，从而抑制AMPs的表达，以促进分枝杆菌的存活。从机制上讲，PRSS1 与 TAK1 结合并破坏 TAK1/TAB1 复合物的形成，从而抑制 TAK1 介导的 NF-κB 通路激活，但 L-丙氨酸与 PRSS1 的相互作用，会禁用 PRSS1 介导的 TAK1/TAB1 复合物形成损伤，从而触发NF-κB 通路的激活诱导 AMP 的表达。此外，抗菌肽基因β-防御素4（Defb4）的缺失会削弱Rv2780在小鼠感染过程中的毒力。 L-丙氨酸和 Rv2780 抑制剂 GWP-042 均对体内结核分枝杆菌感染表现出优异的抑制活性。我们的研究结果确定了一种以前未被认识的机制，即结核分枝杆菌利用其自身的丙氨酸脱氢酶来抑制宿主免疫，并为开发针对结核分枝杆菌的有效免疫调节剂提供了相关见解。