The Metallophore Staphylopine Enables Staphylococcus aureus To Compete with the Host for Zinc and Overcome Nutritional Immunity.
The Metallophore Staphylopine Enables Staphylococcus aureus To Compete with the Host for Zinc and Overcome Nutritional Immunity.
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DOI：
10.1128/mbio.01281-17
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发表时间：
2017-10-31
期刊：
影响因子：
6.4
通讯作者：
Kehl-Fie TE
中科院分区：
文献类型：
--
作者：
Grim KP;San Francisco B;Radin JN;Brazel EB;Kelliher JL;Párraga Solórzano PK;Kim PC;McDevitt CA;Kehl-Fie TE
在感染期间，宿主隔离必要的营养物质，如锌，以对抗入侵的微生物。尽管免疫效应蛋白钙保护素能够以皮下摩尔亲和力结合锌，但金黄色葡萄球菌仍能够成功地与宿主竞争锌。然而，金黄色葡萄球菌表达的锌进口商仍不为人知。我们的研究表明，金黄色葡萄球菌拥有两个进口体AdcABC和CntABCDF，它们是对锌限制的反应而诱导的。虽然AdcABC与其他细菌中已知的锌进口子相似，但CntABCDF之前并未与锌的获得有关。这两个系统的同时丧失严重损害了金黄色葡萄球菌获得锌并在缺锌环境中生长的能力。进一步的研究发现，CNT系统负责金黄色葡萄球菌在培养过程中与钙保护素竞争锌的能力，并有助于在感染期间获得锌。Cnt基因座还使金黄色葡萄球菌能够产生广谱金属载体葡萄球菌。与CNT转运蛋白类似，金黄色葡萄球菌在培养和感染期间都会严重削弱抵抗宿主施加的锌饥饿的能力。进一步的调查发现，葡萄碱和碳纳米管进口体的功能类似于基于铁载体的铁获取系统，以促进金黄色葡萄球菌获取锌。在广泛的革兰氏阳性和革兰氏阴性细菌中发现了类似的系统，这表明这种新型的锌进口体广泛地促进了细菌引起感染的能力。宿主对感染的一个关键防御措施是限制锌的可获得性。尽管免疫效应器钙保护素对锌具有亚皮摩尔亲和力，但金黄色葡萄球菌可以成功地竞争这种重要的金属。这里，我们描述了金黄色葡萄球菌拥有的两家锌进口商AdcABC和CntABCDF，后者此前并未与锌收购有关。金黄色葡萄球菌与宿主竞争锌的能力取决于CntABCDF和金属载体葡萄球菌，在培养和感染期间都是如此。这些结果扩展了细菌获得锌的机制，超出了ADC类系统，并表明病原体在感染期间利用类似于基于铁载体的铁获得的策略来获得其他必需金属。葡萄球菌碱合成机制存在于不同的细菌集合中，这表明这个新的锌进口子家族广泛地促进了许多病原体导致感染的能力。
During infection, the host sequesters essential nutrients, such as zinc, to combat invading microbes. Despite the ability of the immune effector protein calprotectin to bind zinc with subpicomolar affinity, Staphylococcus aureus is able to successfully compete with the host for zinc. However, the zinc importers expressed by S. aureus remain unknown. Our investigations have revealed that S. aureus possesses two importers, AdcABC and CntABCDF, which are induced in response to zinc limitation. While AdcABC is similar to known zinc importers in other bacteria, CntABCDF has not previously been associated with zinc acquisition. Concurrent loss of the two systems severely impairs the ability of S. aureus to obtain zinc and grow in zinc-limited environments. Further investigations revealed that the Cnt system is responsible for the ability of S. aureus to compete with calprotectin for zinc in culture and contributes to acquisition of zinc during infection. The cnt locus also enables S. aureus to produce the broad-spectrum metallophore staphylopine. Similarly to the Cnt transporter, loss of staphylopine severely impairs the ability of S. aureus to resist host-imposed zinc starvation, both in culture and during infection. Further investigations revealed that together staphylopine and the Cnt importer function analogously to siderophore-based iron acquisition systems in order to facilitate zinc acquisition by S. aureus. Analogous systems are found in a broad range of Gram-positive and Gram-negative bacterial pathogens, suggesting that this new type of zinc importer broadly contributes to the ability of bacteria to cause infection. A critical host defense against infection is the restriction of zinc availability. Despite the subpicomolar affinity of the immune effector calprotectin for zinc, Staphylococcus aureus can successfully compete for this essential metal. Here, we describe two zinc importers, AdcABC and CntABCDF, possessed by S. aureus, the latter of which has not previously been associated with zinc acquisition. The ability of S. aureus to compete with the host for zinc is dependent on CntABCDF and the metallophore staphylopine, both in culture and during infection. These results expand the mechanisms utilized by bacteria to obtain zinc, beyond Adc-like systems, and demonstrate that pathogens utilize strategies similar to siderophore-based iron acquisition to obtain other essential metals during infection. The staphylopine synthesis machinery is present in a diverse collection of bacteria, suggesting that this new family of zinc importers broadly contributes to the ability of numerous pathogens to cause infection.