Tuberculosis Research Program at the Centenary Institute, The University of Sydney, Camperdown, NSW, Australia.
Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
FEBS J. 2022 Feb;289(3):671-681. doi: 10.1111/febs.16209. Epub 2021 Sep 28.
Iron homeostasis is essential for both sides of the host-pathogen interface. Restricting access of iron slows bacterial growth while iron is also a necessary cofactor for host immunity. Haem oxygenase 1 (HMOX1) is a critical regulator of iron homeostasis that catalyses the liberation of iron during degradation of haem. It is also a stress-responsive protein that can be rapidly upregulated and confers protection to the host. Although a protective role of HMOX1 has been demonstrated in a variety of diseases, the role of HMOX1 in Mycobacterium tuberculosis infection is equivocal across experiments with different host-pathogen combinations. Here, we use the natural host-pathogen pairing of the zebrafish-Mycobacterium marinum infection platform to study the role of zebrafish haem oxygenase in mycobacterial infection. We identify zebrafish Hmox1a as the relevant functional paralog of mammalian HMOX1 and demonstrate a conserved role for Hmox1a in protecting the host from M. marinum infection. Using genetic and chemical tools, we show zebrafish Hmox1a protects the host against M. marinum infection by reducing infection-induced iron accumulation and ferrostatin-sensitive cell death.
铁稳态对于宿主-病原体界面的双方都至关重要。限制铁的获取会减缓细菌的生长，而铁也是宿主免疫的必要辅因子。血红素加氧酶 1（HMOX1）是铁稳态的关键调节剂，它在血红素降解过程中催化铁的释放。它也是一种应激反应蛋白，可以被快速上调，并为宿主提供保护。尽管 HMOX1 在多种疾病中表现出保护作用，但在不同宿主-病原体组合的实验中，HMOX1 在结核分枝杆菌感染中的作用是有争议的。在这里，我们使用斑马鱼-分枝杆菌感染平台的天然宿主-病原体配对来研究斑马鱼血红素加氧酶在分枝杆菌感染中的作用。我们确定斑马鱼 Hmox1a 是哺乳动物 HMOX1 的相关功能同源物，并证明 Hmox1a 在保护宿主免受 M. marinum 感染方面具有保守作用。我们使用遗传和化学工具表明，斑马鱼 Hmox1a 通过减少感染诱导的铁积累和铁蛋白敏感细胞死亡来保护宿主免受 M. marinum 感染。
