Department of Microbiology and Immunology, University of Michigan Medical School, 5641 Medical Sciences Bldg. II, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.
Infect Immun. 2011 Mar;79(3):1225-35. doi: 10.1128/IAI.01222-10. Epub 2011 Jan 10.
Uropathogenic Escherichia coli (UPEC), the predominant cause of uncomplicated urinary tract infection (UTI), utilizes an array of outer membrane iron receptors to facilitate siderophore and heme import from within the iron-limited urinary tract. While these systems are required for UPEC in vivo fitness and are assumed to be functionally redundant, the relative contributions of specific receptors to pathogenesis are unknown. To delineate the relative roles of distinct UPEC iron acquisition systems in UTI, isogenic mutants in UPEC strain CFT073 or 536 lacking individual receptors were competed against one another in vivo in a series of mixed infections. When combinations of up to four mutants were coinoculated using a CBA/J mouse model of ascending UTI, catecholate receptor mutants (ΔfepA, Δiha, and ΔiroN mutants) were equally fit, suggesting redundant function. However, noncatecholate siderophore receptor mutants, including the ΔiutA aerobactin receptor mutant and the ΔfyuA yersiniabactin receptor mutant, were frequently outcompeted by coinoculated mutants, indicating that these systems contribute more significantly to UPEC iron acquisition in vivo. A tissue-specific preference for heme acquisition was also observed, as a heme uptake-deficient Δhma ΔchuA double mutant was outcompeted by siderophore receptor mutants specifically during kidney colonization. The relative contribution of each receptor to UTI only partially correlated with in vivo levels of receptor gene expression, indicating that other factors likely contributed to the observed fitness differences. Overall, our results suggest that UPEC iron receptors provide both functional redundancy and niche specificity for this pathogen as it colonizes distinct sites within the urinary tract.
尿路致病性大肠杆菌（UPEC）是引起单纯性尿路感染（UTI）的主要原因，它利用一系列外膜铁受体来促进从铁限制的泌尿道内摄取铁载体和血红素。虽然这些系统对于 UPEC 在体内的适应性是必需的，并且假定它们在功能上是冗余的，但特定受体对发病机制的相对贡献尚不清楚。为了阐明 UPEC 铁摄取系统在 UTI 中的相对作用，在 CBA/J 小鼠上行性尿路感染模型中，对 CFT073 或 536 株 UPEC 的同源突变体进行了体内竞争实验，这些突变体分别缺失单个受体。当使用多达四个突变体的组合进行共接种时，儿茶酚受体突变体（ΔfepA、Δiha 和 ΔiroN 突变体）具有相同的适应性，表明功能上是冗余的。然而，非儿茶酚铁载体受体突变体，包括 aerobactin 受体突变体 ΔiutA 和 yersiniabactin 受体突变体 ΔfyuA，经常被共接种的突变体所淘汰，这表明这些系统在体内对 UPEC 铁摄取的贡献更为显著。还观察到对血红素摄取的组织特异性偏好，因为血红素摄取缺陷型 Δhma ΔchuA 双突变体在肾脏定植期间被铁载体受体突变体特异性淘汰。每个受体对 UTI 的相对贡献仅部分与体内受体基因表达水平相关，这表明其他因素可能导致了观察到的适应性差异。总的来说，我们的结果表明，UPEC 铁受体为该病原体在泌尿道内不同部位定植提供了功能冗余和生态位特异性。
