Ferritinophagy drives uropathogenic Escherichia coli persistence in bladder epithelial cells
Ferritinophagy drives uropathogenic Escherichia coli persistence in bladder epithelial cells
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DOI：
10.1080/15548627.2016.1160176
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Mysorekar, Indira U.
中科院分区：
文献类型：
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作者：
Bauckman, Kyle A.;Mysorekar, Indira U.
自噬是一种细胞循环途径，在许多情况下，通过降解病原体来保护宿主细胞免受感染。然而，尿路致病性大肠杆菌（UPEC），尿路感染（UTI）的主要原因，通过在自噬体内形成储库而持续存在于尿路上皮（尿路上皮）内。铁是宿主和病原体的重要营养物质，调节铁的有效性是宿主防御病原体的关键。铁的体内平衡取决于与铁结合的铁蛋白穿梭到溶酶体进行回收，这一过程称为铁蛋白吞噬（选择性自噬的一种形式）。在这里，我们证明了第一次，UPEC穿梭与铁蛋白结合的铁进入自噬体和溶酶体车厢内的尿路上皮。尿路上皮细胞中的铁过载以NCOA 4依赖性方式诱导铁蛋白吞噬，导致UPEC的铁可用性增加，引发细菌过度增殖和宿主细胞死亡。添加甚至中等水平的铁足以增加和延长细菌负荷。此外，我们表明，由于铁超载的溶酶体损伤是导致宿主细胞死亡的具体机制。值得注意的是，我们证明了宿主细胞死亡和细菌负荷可以通过抑制自噬或抑制铁调节蛋白或螯合铁来逆转。总之，我们的研究结果表明，UPEC坚持在宿主细胞中利用铁蛋白吞噬。因此，调节膀胱中的铁水平可以提供控制UPEC持续性、上皮细胞死亡和复发性UTI的治疗途径。
Autophagy is a cellular recycling pathway, which in many cases, protects host cells from infections by degrading pathogens. However, uropathogenic Escherichia coli (UPEC), the predominant cause of urinary tract infections (UTIs), persist within the urinary tract epithelium (urothelium) by forming reservoirs within autophagosomes. Iron is a critical nutrient for both host and pathogen, and regulation of iron availability is a key host defense against pathogens. Iron homeostasis depends on the shuttling of iron-bound ferritin to the lysosome for recycling, a process termed ferritinophagy (a form of selective autophagy). Here, we demonstrate for the first time that UPEC shuttles with ferritin-bound iron into the autophagosomal and lysosomal compartments within the urothelium. Iron overload in urothelial cells induces ferritinophagy in an NCOA4-dependent manner causing increased iron availability for UPEC, triggering bacterial overproliferation and host cell death. Addition of even moderate levels of iron is sufficient to increase and prolong bacterial burden. Furthermore, we show that lysosomal damage due to iron overload is the specific mechanism causing host cell death. Significantly, we demonstrate that host cell death and bacterial burden can be reversed by inhibition of autophagy or inhibition of iron-regulatory proteins, or chelation of iron. Together, our findings suggest that UPEC persist in host cells by taking advantage of ferritinophagy. Thus, modulation of iron levels in the bladder may provide a therapeutic avenue to controlling UPEC persistence, epithelial cell death, and recurrent UTIs.