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Type I Interferon Response Dysregulates Host Iron Homeostasis and Enhances Candida glabrata Infection.
Cell Host & Microbe ( IF 30.3 ) Pub Date : 2020-02-05 , DOI: 10.1016/j.chom.2020.01.023
Michael Riedelberger 1 , Philipp Penninger 1 , Michael Tscherner 1 , Markus Seifert 2 , Sabrina Jenull 1 , Carina Brunnhofer 3 , Bernhard Scheidl 1 , Irina Tsymala 1 , Christelle Bourgeois 1 , Andriy Petryshyn 1 , Walter Glaser 1 , Andreas Limbeck 3 , Birgit Strobl 4 , Guenter Weiss 2 , Karl Kuchler 1
Affiliation  

Type I interferons (IFNs-I) fulfil multiple protective functions during pathogenic infections, but they can also cause detrimental effects and enhance immunopathology. Here, we report that IFNs-I promote the dysregulation of iron homeostasis in macrophages during systemic infections with the intracellular pathogen Candida glabrata, leading to fungal survival and persistence. By engaging JAK1, IFNs-I disturb the balance of the transcriptional activator NRF2 and repressor BACH1 to induce downregulation of the key iron exporter Fpn1 in macrophages. This leads to enhanced iron accumulation in the phagolysosome and failure to restrict fungal access to iron pools. As a result, C. glabrata acquires iron via the Sit1/Ftr1 iron transporter system, facilitating fungal intracellular replication and immune evasion. Thus, IFNs-I are central regulators of iron homeostasis, which can impact infection, and restricting iron bioavailability may offer therapeutic strategies to combat invasive fungal infections.

中文翻译:

I 型干扰素反应使宿主铁稳态失调并增强光滑念珠菌感染。

I 型干扰素 (IFN-I) 在病原性感染期间发挥多种保护功能,但它们也可能造成有害影响并增强免疫病理学。在此,我们报告在细胞内病原体光滑念珠菌全身感染期间,IFN-I 促进巨噬细胞中铁稳态的失调,导致真菌存活和持续存在。通过与 JAK1 结合,IFN-I 扰乱转录激活因子 NRF2 和阻遏因子 BACH1 的平衡,从而诱导巨噬细胞中关键铁输出蛋白 Fpn1 的下调。这导致吞噬溶酶体中铁的积累增加,并且无法限制真菌进入铁池。因此,光滑念珠菌通过 Sit1/Ftr1 铁转运系统获取铁,促进真菌细胞内复制和免疫逃避。因此,
更新日期:2020-02-20
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