Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Clinical and Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Elife. 2024 Nov 4;13:RP92737. doi: 10.7554/eLife.92737.
Deeper understanding of the crosstalk between host cells and (Mtb) provides crucial guidelines for the rational design of novel intervention strategies against tuberculosis (TB). Mycobacteria possess a unique complex cell wall with arabinogalactan (AG) as a critical component. AG has been identified as a virulence factor of Mtb which is recognized by host galectin-9. Here, we demonstrate that galectin-9 directly inhibited mycobacterial growth through AG-binding property of carbohydrate-recognition domain 2. Furthermore, IgG antibodies with AG specificity were detected in the serum of TB patients. Based on the interaction between galectin-9 and AG, we developed a monoclonal antibody (mAb) screening assay and identified AG-specific mAbs which profoundly inhibit Mtb growth. Mechanistically, proteomic profiling and morphological characterizations revealed that AG-specific mAbs regulate AG biosynthesis, thereby inducing cell wall swelling. Thus, direct AG-binding by galectin-9 or antibodies contributes to protection against TB. Our findings pave the way for the rational design of novel immunotherapeutic strategies for TB control.
深入了解宿主细胞与（结核分枝杆菌）之间的串扰为合理设计针对结核病（TB）的新型干预策略提供了重要指导。分枝杆菌具有独特的复杂细胞壁，阿拉伯半乳聚糖（AG）是其关键成分。AG 已被确定为 Mtb 的毒力因子，被宿主半乳凝集素-9 识别。在这里，我们证明半乳凝集素-9 通过碳水化合物识别结构域 2 的 AG 结合特性直接抑制分枝杆菌的生长。此外，在 TB 患者的血清中检测到具有 AG 特异性的 IgG 抗体。基于半乳凝集素-9 和 AG 之间的相互作用，我们开发了一种单克隆抗体（mAb）筛选测定法，并鉴定出具有强烈抑制 Mtb 生长的 AG 特异性 mAb。从机制上讲，蛋白质组学分析和形态特征揭示了 AG 特异性 mAb 调节 AG 生物合成，从而诱导细胞壁肿胀。因此，半乳凝集素-9 或抗体的直接 AG 结合有助于预防 TB。我们的研究结果为合理设计针对结核病控制的新型免疫治疗策略铺平了道路。
