Tuberculosis (TB) is the leading cause of mortality among infectious diseases worldwide. The study of molecular targets for therapy and diagnosis suggested that Notch signaling is an important pathway for the maintenance of the immune response during Mycobacterium tuberculosis (Mtb) infection. We evaluated the participation of the Notch pathway in the modulation of immune response during Mtb infection, and observed that patients with active TB had increased DLL4 expression in intermediate and non-classic monocytes. Further, patients with moderate and advanced lung injury have higher Notch1 expression in CD4+ T cells when compared to patients with a minimal lung injury. When we considered the severity of disease in active TB patients, the expression of the DLL4 in intermediate monocytes and the expression of Notch1 in CD4+ T cells are positively correlated with the degree of lung injury. In vitro, PBMCs treated with the Notch pharmacological inhibitor reduced the production of IL-17A and IL-2, whereas anti-hDLL4 treatment promoted a significant increase in TNF-α and phagocytosis. We suggest that Notch1 and DLL4 are associated with immune response activation in human tuberculosis, and can be a novel target to be exploited in the future in the searching of biomarkers.

中文翻译：

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NOTCH1 和 DLL4 参与人类结核病进展和免疫反应激活

结核病（TB）是全球传染病死亡的主要原因。对用于治疗和诊断的分子靶点的研究表明，Notch 信号传导是在结核分枝杆菌 (Mtb) 感染期间维持免疫反应的重要途径。我们评估了 Notch 通路在 Mtb 感染期间对免疫反应调节的参与，并观察到活动性 TB 患者在中间和非经典单核细胞中的 DLL4 表达增加。此外，与轻度肺损伤患者相比，中度和晚期肺损伤患者在 CD4+ T 细胞中的 Notch1 表达更高。当我们考虑活动性结核病患者的疾病严重程度时，中间单核细胞中DLL4的表达和CD4+ T细胞中Notch1的表达与肺损伤程度呈正相关。在体外，用 Notch 药理学抑制剂处理的 PBMC 减少了 IL-17A 和 IL-2 的产生，而抗 hDLL4 处理促进了 TNF-α 和吞噬作用的显着增加。我们认为 Notch1 和 DLL4 与人类结核病的免疫反应激活有关，并且可以成为未来寻找生物标志物的新靶点。