Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Immunology and Molecular Pathogenesis Graduate Program, Emory University School of Medicine, Atlanta, Georgia, United States of America.
PLoS Pathog. 2023 May 18;19(5):e1011387. doi: 10.1371/journal.ppat.1011387. eCollection 2023 May.
Infections caused by members of the mycobacterium tuberculosis complex [MTC] and nontuberculous mycobacteria [NTM] can induce widespread morbidity and mortality in people. Mycobacterial infections cause both a delayed immune response, which limits rate of bacterial clearance, and formation of granulomas, which contain bacterial spread, but also contribute to lung damage, fibrosis, and morbidity. Granulomas also limit access of antibiotics to bacteria, which may facilitate development of resistance. Bacteria resistant to some or all antibiotics cause significant morbidity and mortality, and newly developed antibiotics readily engender resistance, highlighting the need for new therapeutic approaches. Imatinib mesylate, a cancer drug used to treat chronic myelogenous leukemia [CML] that targets Abl and related tyrosine kinases, is a possible host-directed therapeutic [HDT] for mycobacterial infections, including those causing TB. Here, we use the murine Mycobacterium marinum [Mm] infection model, which induces granulomatous tail lesions. Based on histological measurements, imatinib reduces both lesion size and inflammation of surrounding tissue. Transcriptomic analysis of tail lesions indicates that imatinib induces gene signatures indicative of immune activation and regulation at early time points post infection that resemble those seen at later ones, suggesting that imatinib accelerates but does not substantially alter anti-mycobacterial immune responses. Imatinib likewise induces signatures associated with cell death and promotes survival of bone marrow-derived macrophages [BMDMs] in culture following infection with Mm. Notably, the capacity of imatinib to limit formation and growth of granulomas in vivo and to promote survival of BMDMs in vitro depends upon caspase 8, a key regulator of cell survival and death. These data provide evidence for the utility of imatinib as an HDT for mycobacterial infections in accelerating and regulating immune responses, and limiting pathology associated with granulomas, which may mitigate post-treatment morbidity.
分枝杆菌复合体 [MTC] 和非结核分枝杆菌 [NTM] 引起的感染可导致人类广泛的发病率和死亡率。分枝杆菌感染会引起延迟的免疫反应，从而限制细菌清除率，并形成含有细菌扩散的肉芽肿，但也会导致肺部损伤、纤维化和发病率增加。肉芽肿也限制了抗生素对细菌的接触，这可能促进了耐药性的发展。对一些或所有抗生素耐药的细菌会导致严重的发病率和死亡率，而新开发的抗生素容易产生耐药性，这突出表明需要新的治疗方法。甲磺酸伊马替尼是一种用于治疗慢性髓性白血病 [CML] 的抗癌药物，其靶向 Abl 和相关酪氨酸激酶，是分枝杆菌感染的潜在宿主导向治疗 [HDT]，包括引起结核病的感染。在这里，我们使用了诱导肉芽肿尾巴病变的鼠分枝杆菌 [Mm] 感染模型。基于组织学测量，伊马替尼可减少病变大小和周围组织的炎症。尾巴病变的转录组分析表明，伊马替尼在感染后早期诱导与晚期相似的免疫激活和调节基因特征，表明伊马替尼可加速但不会显著改变抗分枝杆菌免疫反应。伊马替尼同样诱导与细胞死亡相关的特征，并在感染 Mm 后促进骨髓来源的巨噬细胞 [BMDM] 的存活。值得注意的是，伊马替尼在体内限制肉芽肿的形成和生长以及在体外促进 BMDM 的存活的能力取决于半胱天冬酶 8，这是细胞存活和死亡的关键调节剂。这些数据为伊马替尼作为分枝杆菌感染的 HDT 的实用性提供了证据，可加速和调节免疫反应，并限制与肉芽肿相关的病理学，从而减轻治疗后的发病率。
