Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
mBio. 2023 Apr 25;14(2):e0349622. doi: 10.1128/mbio.03496-22. Epub 2023 Feb 28.
Despite numerous advances in tuberculosis (TB) drug development, long treatment durations have led to the emergence of multidrug resistance, which poses a major hurdle to global TB control. Shortening treatment time therefore remains a top priority. Host-directed therapies that promote bacterial clearance and/or lung health may improve the efficacy and treatment duration of tuberculosis antibiotics. We recently discovered that inhibition of the integrated stress response, which is abnormally activated in tuberculosis and associated with necrotic granuloma formation, reduced bacterial numbers and lung inflammation in mice. Here, we evaluated the impact of the integrated stress response (ISR) inhibitor ISRIB, administered as an adjunct to standard tuberculosis antibiotics, on bacterial clearance, relapse, and lung pathology in a mouse model of tuberculosis. Throughout the course of treatment, ISRIB robustly lowered bacterial burdens compared to the burdens with standard TB therapy alone and accelerated the time to sterility in mice, as demonstrated by significantly reduced relapse rates after 4 months of treatment. In addition, mice receiving adjunctive ISRIB tended to have reduced lung necrosis and inflammation. Together, our findings identify the ISR pathway as a promising therapeutic target with the potential to shorten TB treatment durations and improve lung health. Necrosis of lung lesions is a hallmark of tuberculosis (TB) that promotes bacterial growth, dissemination, and transmission. This process is driven by the persistent hyperactivation of the integrated stress response (ISR) pathway. Here, we show that adjunctive ISR inhibition during standard antibiotic therapy accelerates bacterial clearance and reduces immunopathology in a clinically relevant mouse model of TB, suggesting that host-directed therapies that de-escalate these pathological stress responses may shorten TB treatment durations. Our findings present an important conceptual advance toward overcoming the challenge of improving TB therapy and lowering the global burden of disease.
尽管在结核病（TB）药物研发方面取得了许多进展，但长期的治疗时间导致了耐多药的出现，这对全球结核病控制构成了重大障碍。因此，缩短治疗时间仍然是当务之急。促进细菌清除和/或肺部健康的宿主定向疗法可能会提高结核病抗生素的疗效和治疗持续时间。我们最近发现，抑制整合应激反应（ISR），该反应在结核病中异常激活，并与坏死性肉芽肿形成有关，可以减少小鼠中的细菌数量和肺部炎症。在这里，我们评估了整合应激反应（ISR）抑制剂 ISRIB 作为标准结核病抗生素的辅助治疗对结核病小鼠模型中的细菌清除、复发和肺部病理学的影响。在整个治疗过程中，与单独使用标准 TB 治疗相比，ISRIB 可显著降低细菌负荷，并加速小鼠达到无菌状态，这体现在治疗 4 个月后复发率显著降低。此外，接受辅助性 ISRIB 治疗的小鼠肺部坏死和炎症减少。总的来说，我们的发现确定了 ISR 途径是一种有前途的治疗靶点，有可能缩短结核病的治疗时间并改善肺部健康。肺病变的坏死是结核病（TB）的一个标志，它促进了细菌的生长、传播和传播。这个过程是由整合应激反应（ISR）途径的持续过度激活驱动的。在这里，我们表明，在标准抗生素治疗期间辅助性 ISR 抑制加速了临床相关的 TB 小鼠模型中的细菌清除并减少了免疫病理学，这表明减轻这些病理应激反应的宿主定向疗法可能会缩短结核病的治疗时间。我们的研究结果为克服改善结核病治疗和降低全球疾病负担的挑战提供了一个重要的概念性进展。
