Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection.
Sensing of mycobacterial arabinogalactan by galectin-9 exacerbates mycobacterial infection.
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半乳糖凝集素 9 对分枝杆菌阿拉伯半乳聚糖的感知加剧了分枝杆菌感染
DOI：
10.15252/embr.202051678
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发表时间：
2021-07-05
期刊：
影响因子：
7.7
通讯作者：
Ge B
中科院分区：
文献类型：
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作者：
Wu X;Wu Y;Zheng R;Tang F;Qin L;Lai D;Zhang L;Chen L;Yan B;Yang H;Wang Y;Li F;Zhang J;Wang F;Wang L;Cao Y;Ma M;Liu Z;Chen J;Huang X;Wang J;Jin R;Wang P;Sun Q;Sha W;Lyu L;Moura-Alves P;Dorhoi A;Pei G;Zhang P;Chen J;Gao S;Randow F;Zeng G;Chen C;Ye XS;Kaufmann SHE;Liu H;Ge B
分枝杆菌阿拉伯半乳聚糖（AG）是分枝杆菌的基本细胞壁组分，也是抗结核（TB）药物开发的常见结构和生物合成靶标。在这里，我们报告了分枝杆菌AG被半乳糖凝集素-9识别并加剧分枝杆菌感染。施用AG特异性适体可抑制结核分枝杆菌（Mtb）或牛分枝杆菌BCG引起的细胞浸润，并适度增加Mtb感染小鼠或海洋分枝杆菌感染斑马鱼的存活率。AG以高亲和力与半乳糖凝集素-9的碳水化合物识别结构域（CRD）2相互作用，半乳糖凝集素-9通过CRD 2与转化生长因子β激活的激酶1（TAK 1）结合，引发细胞外信号调节激酶（ERK）的后续激活以及诱导基质金属蛋白酶（MMP）的表达。此外，半乳糖凝集素-9的缺失或MMP的抑制阻断了AG诱导的肺病理损伤，并且AG-半乳糖凝集素-9轴使小鼠中Mtb感染的过程简化。这些结果表明，AG是分枝杆菌的重要毒力因子，半乳糖凝集素-9是Mtb和其他分枝杆菌的新型受体，为开发新型有效的TB免疫调节剂铺平了道路。阿拉伯半乳聚糖是分枝杆菌的毒力因子。半乳糖凝集素-9与分枝杆菌阿拉伯半乳聚糖的结合通过TAK 1-ERK信号传导触发基质金属蛋白酶，这促进分枝杆菌感染并增加肺损伤。
Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio‐synthetical target for anti‐tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin‐9 and exacerbates mycobacterial infection. Administration of AG‐specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb‐infected mice or Mycobacterium marinum‐infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin‐9 with high affinity, and galectin‐9 associates with transforming growth factor β‐activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal‐regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin‐9 or inhibition of MMPs blocks AG‐induced pathological impairments in the lung, and the AG‐galectin‐9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin‐9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators. Arabinogalactan is a virulence factor of mycobacteria. Binding of galectin‐9 to mycobacterial arabinogalactan triggers matrix metalloproteinases via TAK1‐ERK signaling, which promotes mycobacterial infection and increases lung injury.
DOI：
10.1159/000163217
发表时间：
2009
期刊：
ORL; journal for oto-rhino-laryngology and its related specialties
影响因子：
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作者：
Skipper JB;McNally LR;Rosenthal EL;Wang W;Buchsbaum DJ
通讯作者：
Buchsbaum DJ