Haschka David, Nairz Manfred, Demetz Egon, Wienerroither Sebastian, Decker Thomas, Weiss Günter
Department of Internal Medicine VI, Medical University of Innsbruck, Anichstraße 35, A - 6020 Innsbruck, Austria.
Metallomics. 2015 Jun;7(6):1036-45. doi: 10.1039/c4mt00328d.
Due to its multiple roles for the proliferation and pathogenicity of many microbes on the one hand and via modulation of immune effector functions on the other hand the control over iron homeostasis is thought to play a decisive role in the course of infections. Diversion of cellular iron traffic is considered as an important defense mechanism of macrophages to reduce metal availability for intracellular bacteria residing in the phagosome. However, evidence is lacking whether such alterations of iron homeostasis also become evident upon infection with bacteria gaining access to the cytosol like Listeria monocytogenes. Here we show that infection of macrophages with L. monocytogenes triggers the expression of the major cellular iron exporter ferroportin1 and induces cellular iron egress. As the growth of Listeria within macrophages is promoted by iron, stimulation of ferroportin1 functionality limits the availability of the metal for Listeria residing in the cytoplasm, whereas ferroportin1 degradation upon hepcidin treatment increases intracellular bacterial growth. In parallel to an increase of ferroportin1 expression, infected macrophages induce anti-microbial immune effector mechanisms such as TNFα formation or NO expression which are aggravated upon iron deficiency. These adaptive changes of iron homeostasis and immune response pathways are only found in macrophages infected with Listeria which express listeriolysin O and are therefore able to escape from the phagosome to the cytoplasm. Listeriolysin O deficient Listeria which are restricted to the phagosome are even killed by excess iron which may be based on "iron intoxification" via macrophage radical formation, because iron supplementation in that setting is paralleled by increased ROS formation. Our results indicate that ferroportin1 mediated iron export is a nutritional immune effector pathway to control infection with Listeria residing in the cytoplasm, whereas a different strategy is observed in mutant Listeria restricted to the phagosome, where iron remains in the macrophages likewise contributing to ROS mediated intoxification of bacteria.
一方面，由于铁稳态对多种微生物的增殖和致病性具有多种作用，另一方面又通过调节免疫效应功能，因此铁稳态的控制被认为在感染过程中起决定性作用。细胞铁转运的改变被认为是巨噬细胞的一种重要防御机制，可减少吞噬体内胞内细菌可利用的金属。然而，对于像单核细胞增生李斯特菌这样能够进入胞质溶胶的细菌感染后，铁稳态的这种改变是否也会明显表现出来，目前还缺乏证据。在此我们表明，巨噬细胞被单核细胞增生李斯特菌感染会触发主要的细胞铁输出蛋白铁转运蛋白1的表达并诱导细胞铁外流。由于铁可促进李斯特菌在巨噬细胞内生长，刺激铁转运蛋白1的功能会限制细胞质中李斯特菌可利用的金属量，而铁调素处理后铁转运蛋白1的降解则会增加细胞内细菌的生长。与铁转运蛋白1表达增加同时发生的是，被感染的巨噬细胞会诱导抗菌免疫效应机制，如肿瘤坏死因子α的形成或一氧化氮的表达，而缺铁时这些机制会加剧。铁稳态和免疫反应途径的这些适应性变化仅在被表达李斯特菌溶素O因而能够从吞噬体逃逸到细胞质的单核细胞增生李斯特菌感染的巨噬细胞中发现。局限于吞噬体的缺乏李斯特菌溶素O的李斯特菌甚至会被过量的铁杀死，这可能是基于巨噬细胞自由基形成导致的“铁中毒”，因为在这种情况下补充铁的同时会伴随活性氧生成增加。我们的结果表明，铁转运蛋白1介导的铁输出是一种营养免疫效应途径，可控制细胞质中李斯特菌的感染，而在局限于吞噬体的突变李斯特菌中则观察到不同的策略，在这种情况下铁留在巨噬细胞内同样会导致活性氧介导的细菌中毒。
