Mucosal immunization with iron receptor antigens protects against urinary tract infection.
Mucosal immunization with iron receptor antigens protects against urinary tract infection.
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DOI：
10.1371/journal.ppat.1000586
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发表时间：
2009-09
期刊：
影响因子：
6.7
通讯作者：
Mobley HL
中科院分区：
文献类型：
--
作者：
Alteri CJ;Hagan EC;Sivick KE;Smith SN;Mobley HL
由尿路致病性大肠杆菌引起的单纯性尿路感染是需要医疗干预的最常见疾病之一。减少这些感染的发病率和财政负担的预防性疫苗将是有益的。在这里，我们描述了大规模选择过程的结果，该过程结合了生物信息学、基因组学、转录组学和蛋白质组学筛选，从尿路致病性大肠杆菌菌株 CFT073 编码的 5379 种预测蛋白质中鉴定出六种候选疫苗。候选疫苗 ChuA、Hma、Iha、IreA、IroN 和 IutA 都属于参与铁获取的功能分子类别，铁获取是所有微生物发病机制的关键过程。用这些外膜铁受体对 CBA/J 小鼠进行鼻内免疫，引发全身和粘膜免疫反应，包括产生抗原特异性 IgM、IgG 和 IgA 抗体。对疫苗接种的细胞反应的特征是诱导和分泌 IFN-γ 和 IL-17。在六种潜在的候选疫苗中，IreA、Hma 和 IutA 提供了针对实验性感染的显着保护。在免疫动物中，从 IgM 到 IgG 的类别转换以及尿液中抗原特异性 IgA 的产生代表了防止大肠杆菌膀胱定植的免疫学相关性。这些发现是开发预防尿路感染的亚单位疫苗的重要第一步，并证明针对发病机制共同所需的一整类分子如何可能成为对抗感染的基本策略。由于尿路感染 (UTI) 是一个重大的医疗负担，因此开发一种疫苗来预防由大肠杆菌引起的简单尿路感染将是有益的。通过大规模筛选过程，我们统一鉴定了参与铁吸收的蛋白质作为潜在的大肠杆菌疫苗候选者。获取铁是细菌引起感染所需的关键功能。在尿路致病性大肠杆菌中，这种功能是由感染期间从宿主体内清除铁的一系列系统介导的。我们发现，接种这些系统中的某些铁受体足以引发实验性尿路感染的保护性免疫力。抗体反应的诱导在防止感染方面发挥着关键作用，因为抗体类别转换和尿液中抗体的产生与膀胱中细菌数量的减少相关。通过针对参与铁获取的一整类分子而不是单一蛋白质，可以成功识别保护性尿路感染疫苗的成分。这种策略可能是开发疫苗以预防其他病原菌引起的感染的有用方法。
Uncomplicated infections of the urinary tract, caused by uropathogenic Escherichia coli, are among the most common diseases requiring medical intervention. A preventive vaccine to reduce the morbidity and fiscal burden these infections have upon the healthcare system would be beneficial. Here, we describe the results of a large-scale selection process that incorporates bioinformatic, genomic, transcriptomic, and proteomic screens to identify six vaccine candidates from the 5379 predicted proteins encoded by uropathogenic E. coli strain CFT073. The vaccine candidates, ChuA, Hma, Iha, IreA, IroN, and IutA, all belong to a functional class of molecules that is involved in iron acquisition, a process critical for pathogenesis in all microbes. Intranasal immunization of CBA/J mice with these outer membrane iron receptors elicited a systemic and mucosal immune response that included the production of antigen-specific IgM, IgG, and IgA antibodies. The cellular response to vaccination was characterized by the induction and secretion of IFN-γ and IL-17. Of the six potential vaccine candidates, IreA, Hma, and IutA provided significant protection from experimental infection. In immunized animals, class-switching from IgM to IgG and production of antigen-specific IgA in the urine represent immunological correlates of protection from E. coli bladder colonization. These findings are an important first step toward the development of a subunit vaccine to prevent urinary tract infections and demonstrate how targeting an entire class of molecules that are collectively required for pathogenesis may represent a fundamental strategy to combat infections. Because urinary tract infections (UTIs) are a significant healthcare burden, it would be beneficial to develop a vaccine to prevent uncomplicated UTI caused by Escherichia coli. Using a large-scale screening process we uniformly identified proteins involved in iron uptake as potential vaccine candidates against E. coli. Iron acquisition is a critical function required by bacteria in order to cause infections. In uropathogenic Escherichia coli, this function is mediated by a repertoire of systems that scavenge iron from the host during infection. We found that vaccination with certain iron receptors from these systems is sufficient to elicit protective immunity from experimental urinary tract infection. Induction of an antibody response played a key role in protection from infection because antibody class-switching and the production of antibodies in urine correlated with reduced numbers of bacteria in the bladder. By targeting an entire class of molecules involved in iron acquisition instead of a single protein, it was possible to successfully identify components of a protective UTI vaccine. This strategy could be a useful approach in the development of vaccines to prevent infections caused by other pathogenic bacteria.
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影响因子：
3.1
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