Multi‐drug‐resistant tuberculosis is a worldwide problem, and there is an urgent need for host‐derived therapeutic targets, circumventing emerging drug resistance. We have previously shown that hypoxia‐inducible factor‐1α (Hif‐1α) stabilisation helps the host to clear mycobacterial infection via neutrophil activation. However, Hif‐1α stabilisation has also been implicated in chronic inflammatory diseases caused by prolonged neutrophilic inflammation. Comorbid infection and inflammation can be found together in disease settings, and it remains unclear whether Hif‐1α stabilisation would be beneficial in a holistic disease setting. Here, we set out to understand the effects of Hif‐1α on neutrophil behaviour in a comorbid setting by combining two well‐characterised in vivo zebrafish models – TB infection (Mycobacterium marinum infection) and sterile injury (tailfin transection). Using a local Mm infection near to the tailfin wound site caused neutrophil migration between the two sites that was reduced during Hif‐1α stabilisation. During systemic Mm infection, wounding leads to increased infection burden, but the protective effect of Hif‐1α stabilisation remains. Our data indicate that Hif‐1α stabilisation alters neutrophil migration dynamics between comorbid sites and that the protective effect of Hif‐1α against Mm is maintained in the presence of inflammation, highlighting its potential as a host‐derived target against TB infection.

中文翻译：

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Hif-1alpha稳定可防止斑马鱼合并模型中的感染。

多重耐药性结核病是一个世界性的问题，因此迫切需要宿主衍生的治疗靶标，从而规避新出现的耐药性。先前我们已经表明，缺氧诱导因子-1α（Hif-1α）的稳定有助于宿主通过中性粒细胞活化清除分枝杆菌感染。但是，Hif-1α的稳定也与长期嗜中性粒细胞炎症引起的慢性炎症有关。在疾病环境中可以同时发现并存感染和炎症，目前尚不清楚Hif-1α的稳定化对整体疾病环境是否有益。在这里，我们着手通过结合两种特征明确的体内斑马鱼模型–结核感染，了解Hif-1α在共病情况下对嗜中性粒细胞行为的影响。海藻分枝杆菌感染）和无菌性损伤（尾鳍横切）。在尾鳍伤口部位附近使用局部Mm感染导致嗜中性粒细胞在两个部位之间迁移，并在Hif-1α稳定期间减少。在全身性Mm感染期间，受伤会导致感染负担增加，但Hif-1α稳定化的保护作用仍然存在。我们的数据表明，Hif-1α的稳定改变了共病部位之间的嗜中性粒细胞迁移动力学，Hif-1α对Mm的保护作用在发炎的情况下得以维持，突显了其作为宿主来源的抗结核感染靶标的潜力。