Ferrous iron is a significant component of bioavailable iron in cystic fibrosis airways.
Ferrous iron is a significant component of bioavailable iron in cystic fibrosis airways.
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DOI：
10.1128/mbio.00557-13
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发表时间：
2013-08-20
期刊：
影响因子：
6.4
通讯作者：
Newman DK
中科院分区：
文献类型：
--
作者：
Hunter RC;Asfour F;Dingemans J;Osuna BL;Samad T;Malfroot A;Cornelis P;Newman DK
由机会致病菌铜绿假单胞菌引起的慢性生物膜样感染是囊性纤维化（CF）患者死亡的主要原因。虽然从实验室研究中对铜绿假单胞菌了解很多，但对其在体内的经历了解甚少。铁是一个重要的环境参数，被认为在铜绿假单胞菌感染的发展和维持中发挥核心作用，用于合成代谢和信号传导目的。以前的研究集中在三价铁[Fe（III）]作为抗菌治疗的靶点;然而，我们发现CF肺中亚铁[Fe（II）]含量丰富（重症患者平均约为39 µM），并与疾病严重程度显著相关（ρ = −0.56，P = 0.004），而三价铁则不然（ρ = −0.28，P = 0.179）。铜绿假单胞菌基因bqsRS（其转录响应于Fe（II）而上调）的表达在大多数受试患者中较高，表明Fe（II）增加对感染性细菌群体具有生物可利用性。由于限制Fe（III）的获得抑制了铜绿假单胞菌在各种体外有氧系统中的生物膜形成，我们还测试了干扰Fe（II）的获得是否会改善缺氧条件下的生物膜控制;两种铁氧化态的同时螯合导致生物膜积累减少58%，生物膜溶解增加28%，与单独的Fe（III）螯合处理相比有显著改善。这项研究表明，随着感染的进展，受感染宿主环境的化学与微生物群落共同进化，在疾病的不同阶段设计有效的治疗策略时应考虑到这一点。铁是一个重要的环境参数，有助于病原体在感染部位繁殖，包括囊性纤维化（CF）患者。三价铁螯合疗法已被提出作为CF肺部感染的新治疗策略，但到目前为止，尚未在宿主中测量铁氧化态。在研究来自欧洲和美国的多名CF患者的感染肺部粘液时，我们发现随着感染的进展，三价铁和二价铁的浓度和相对比例发生变化;随着时间的推移，二价铁开始主导铁池。这些信息与新型CF治疗剂的设计相关，更广泛地说，与开发慢性CF感染的准确模型相关。
Chronic, biofilm-like infections by the opportunistic pathogen Pseudomonas aeruginosa are a major cause of mortality in cystic fibrosis (CF) patients. While much is known about P. aeruginosa from laboratory studies, far less is understood about what it experiences in vivo. Iron is an important environmental parameter thought to play a central role in the development and maintenance of P. aeruginosa infections, for both anabolic and signaling purposes. Previous studies have focused on ferric iron [Fe(III)] as a target for antimicrobial therapies; however, here we show that ferrous iron [Fe(II)] is abundant in the CF lung (~39 µM on average for severely sick patients) and significantly correlates with disease severity (ρ = −0.56, P = 0.004), whereas ferric iron does not (ρ = −0.28, P = 0.179). Expression of the P. aeruginosa genes bqsRS, whose transcription is upregulated in response to Fe(II), was high in the majority of patients tested, suggesting that increased Fe(II) is bioavailable to the infectious bacterial population. Because limiting Fe(III) acquisition inhibits biofilm formation by P. aeruginosa in various oxic in vitro systems, we also tested whether interfering with Fe(II) acquisition would improve biofilm control under anoxic conditions; concurrent sequestration of both iron oxidation states resulted in a 58% reduction in biofilm accumulation and 28% increase in biofilm dissolution, a significant improvement over Fe(III) chelation treatment alone. This study demonstrates that the chemistry of infected host environments coevolves with the microbial community as infections progress, which should be considered in the design of effective treatment strategies at different stages of disease. Iron is an important environmental parameter that helps pathogens thrive in sites of infection, including those of cystic fibrosis (CF) patients. Ferric iron chelation therapy has been proposed as a novel therapeutic strategy for CF lung infections, yet until now, the iron oxidation state has not been measured in the host. In studying mucus from the infected lungs of multiple CF patients from Europe and the United States, we found that ferric and ferrous iron change in concentration and relative proportion as infections progress; over time, ferrous iron comes to dominate the iron pool. This information is relevant to the design of novel CF therapeutics and, more broadly, to developing accurate models of chronic CF infections.