Metheni Mehdi, Lombès Anne, Bouillaud Frédéric, Batteux Frédéric, Langsley Gordon
Inserm U1016, Cnrs UMR8104, Cochin Institute, Paris, France; Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes - Sorbonne Paris Cité, France.
Cell Microbiol. 2015 Apr;17(4):467-72. doi: 10.1111/cmi.12421. Epub 2015 Feb 26.
Within 2 h of infection by Theileria annulata sporozoites, bovine macrophages display a two- to fourfold increase in transcription of hypoxia inducible factor (HIF-1α). Twenty hours post-invasion sporozoites develop into multi-nucleated macroschizonts that transform the infected macrophage into an immortalized, permanently proliferating, hyper-invasive and disease-causing leukaemia-like cell. Once immortalized Theileria-infected leukocytes can be propagated as cell lines and even though cultivated under normoxic conditions, both infected B cells and macrophages display sustained activation of HIF-1α. Attenuated macrophages used as live vaccines against tropical theileriosis also display HIF-1α activation even though they have lost their tumorigenic phenotype. Here, we review data that ascribes HIF-1α activation to the proliferation status of the infected leukocyte and discuss the possibility that Theileria may have lost its ability to render its host macrophage virulent due to continuous parasite replication in a high Reactive Oxygen Species (ROS) environment. We propose a model where uninfected macrophages have low levels of H2 O2 output, whereas virulent-infected macrophages produce high amounts of H2 O2 . Further increase in H2 O2 output leads to dampening of infected macrophage virulence, a characteristic of disease-resistant macrophages. At the same time exposure to H2 O2 sustains HIF-1α that induces the switch from mitochondrial oxidative phosphorylation to Warburg glycolysis, a metabolic shift that underpins uncontrolled infected macrophage proliferation. We propose that as macroschizonts develop into merozoites and infected macrophage proliferation arrests, HIF-1α levels will decrease and glycolysis will switch back from Warburg to oxidative glycolysis. As Theileria infection transforms its host leukocyte into an aggressive leukaemic-like cell, we propose that manipulating ROS levels, HIF-1α induction and oxidative over Warburg glycolysis could contribute to improved disease control. Finally, as excess amounts of H2 O2 drive virulent Theileria-infected macrophages towards attenuation it highlights how infection-induced pathology and redox balance are intimately linked.
在被环形泰勒虫裂殖子感染后的2小时内，牛巨噬细胞中缺氧诱导因子（HIF-1α）的转录增加了两到四倍。入侵后20小时，裂殖子发育成多核大裂殖体，将被感染的巨噬细胞转化为永生化、持续增殖、高侵袭性且致病的白血病样细胞。一旦被泰勒虫感染的白细胞永生化，就可以作为细胞系进行传代培养，并且即使在常氧条件下培养，被感染的B细胞和巨噬细胞中HIF-1α也会持续激活。用作热带泰勒虫病活疫苗的减毒巨噬细胞，即使已经失去致瘤表型，也会表现出HIF-1α激活。在此，我们回顾了将HIF-1α激活归因于被感染白细胞增殖状态的数据，并讨论了泰勒虫可能由于在高活性氧（ROS）环境中持续的寄生虫复制而丧失使其宿主巨噬细胞具有毒性能力的可能性。我们提出了一个模型，其中未感染的巨噬细胞H2O2产量较低，而有毒性的被感染巨噬细胞产生大量H2O2。H2O2产量的进一步增加会导致被感染巨噬细胞毒性减弱，这是抗病巨噬细胞的一个特征。同时，暴露于H2O2会维持HIF-1α，从而诱导从线粒体氧化磷酸化向瓦氏糖酵解的转变，这种代谢转变是被感染巨噬细胞不受控制增殖的基础。我们认为，随着大裂殖体发育成裂殖子且被感染巨噬细胞的增殖停止，HIF-1α水平将降低，糖酵解将从瓦氏糖酵解切换回氧化糖酵解。由于泰勒虫感染将其宿主白细胞转化为侵袭性白血病样细胞，我们认为操纵ROS水平、HIF-1α诱导以及氧化糖酵解与瓦氏糖酵解的平衡可能有助于改善疾病控制。最后，由于过量的H2O2会促使有毒性的被泰勒虫感染的巨噬细胞减毒，这突出了感染诱导的病理学与氧化还原平衡是如何紧密相连的。
