Copper Resistance Promotes Fitness of Methicillin-Resistant Staphylococcus aureus during Urinary Tract Infection.
Copper Resistance Promotes Fitness of Methicillin-Resistant Staphylococcus aureus during Urinary Tract Infection.
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DOI：
10.1128/mbio.02038-21
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发表时间：
2021-10-26
期刊：
影响因子：
6.4
通讯作者：
Subashchandrabose S
中科院分区：
文献类型：
--
作者：
Saenkham-Huntsinger P;Hyre AN;Hanson BS;Donati GL;Adams LG;Ryan C;Londoño A;Moustafa AM;Planet PJ;Subashchandrabose S
尿路感染（UTI）是影响美国和世界各地人们的最常见的感染性疾病之一。与革兰氏阴性病原体相比，我们对革兰氏阳性细菌尿路病原体引起的UTI期间宿主-病原体相互作用的了解有限。在这里，我们调查了是否铜和主要含铜蛋白，铜蓝蛋白，动员到尿液中自然发生的尿路感染引起的革兰氏阳性尿路病原体的患者。接下来，我们在小鼠模型中探索了在实验性UTI期间铜抗性在耐甲氧西林金黄色葡萄球菌（MRSA）适应性中的作用。我们的研究结果表明，尿铜和铜蓝蛋白含量升高，在尿路感染引起的粪肠球菌，S。金黄色葡萄球菌、epidermidis和S.萨皮提库斯MRSA菌株成功地定殖于雌性CBA小鼠的尿路，选择性诱导肾脏而不是膀胱的炎症。缺乏CopL（一种铜结合细胞表面脂蛋白）和含有CopL的ACME基因组区域的MRSA突变体与亲本菌株相比在小鼠泌尿道中表现出降低的适应性。铜敏感性测定、细胞相关铜和铁含量以及铜胁迫期间铁的生物利用度表明，在S.金黄色。重要的是，与亲本菌株相比，在接受补充铜的小鼠中，缺乏ACME区域的MRSA突变体的相对适应性进一步降低。总之，在由革兰氏阳性病原体引起的UTI期间，铜被动员到尿路，并且铜抗性是UTI期间MRSA的适应性因素。
Urinary tract infection (UTI) is one of the most common infectious conditions affecting people in the United States and around the world. Our knowledge of the host-pathogen interaction during UTI caused by Gram-positive bacterial uropathogens is limited compared to that for Gram-negative pathogens. Here, we investigated whether copper and the primary copper-containing protein, ceruloplasmin, are mobilized to urine during naturally occurring UTI caused by Gram-positive uropathogens in patients. Next, we probed the role of copper resistance in the fitness of methicillin-resistant Staphylococcus aureus (MRSA) during experimental UTI in a murine model. Our findings demonstrate that urinary copper and ceruloplasmin content are elevated during UTI caused by Enterococcus faecalis, S. aureus, S. epidermidis, and S. saprophyticus. MRSA strains successfully colonize the urinary tract of female CBA mice with selective induction of inflammation in the kidneys but not the bladder. MRSA mutants lacking CopL, a copper-binding cell surface lipoprotein, and the ACME genomic region containing copL, exhibit decreased fitness in the mouse urinary tract compared to parental strains. Copper sensitivity assays, cell-associated copper and iron content, and bioavailability of iron during copper stress demonstrate that homeostasis of copper and iron is interlinked in S. aureus. Importantly, relative fitness of the MRSA mutant lacking the ACME region is further decreased in mice that receive supplemental copper compared to the parental strain. In summary, copper is mobilized to the urinary tract during UTI caused by Gram-positive pathogens, and copper resistance is a fitness factor for MRSA during UTI.