Optimization of an Experimental Vaccine To Prevent Escherichia coli Urinary Tract Infection
Optimization of an Experimental Vaccine To Prevent Escherichia coli Urinary Tract Infection
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DOI：
10.1128/mbio.00555-20
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发表时间：
2020-03-01
期刊：
影响因子：
6.4
通讯作者：
Mobley, Harry L. T.
中科院分区：
文献类型：
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作者：
Forsyth, Valerie S.;Himpsl, Stephanie D.;Mobley, Harry L. T.
尿路感染（UTI）影响了一半的妇女在其一生中至少一次。产超广谱β-内酰胺酶菌株数量的增加和尿路致病性大肠杆菌（UPEC）（UTI最常见的病原体）对碳青霉烯类耐药的可能性，迫切需要开发疫苗。用与霍乱毒素缀合的UPEC外膜铁受体FyuA、Hma、IreA和lutA鼻内免疫小鼠，在用UPEC菌株CFT 073或菌株536攻击的条件下在膀胱或肾脏中提供保护。基于这些数据，我们试图优化疫苗接种途径（肌内、鼻内或皮下）与适用于人的佐剂的组合，包括氢氧化铝凝胶（明矾）、单磷酰脂质A（MPLA）、非甲基化CpG合成寡脱氧核苷酸（CpG）、聚肌苷酸：聚胞苷酸（polyIC）和突变的热不稳定E.螺旋肠毒素（dmLT）。鼻内接种dmLT-lutA和dmLT-Hma的小鼠显示膀胱定殖显著降低（分别为86倍和32倍），40%至42%的小鼠未检测到CFU。用CpG-lutA和polyIC-lutA鼻内接种小鼠分别显著降低肾脏定殖（131倍）和尿液CFU（22倍）。dmLT在鼻内免疫的小鼠中产生了最稳定的抗体应答，而MPLA和明矾在肌内免疫时产生了更高浓度的抗原特异性血清IgG。基于这些结果，我们得出结论，鼻内施用与dmLT佐剂配制的Hma或lutA提供了对UPEC UTI的最大保护。这份报告推进了我们在针对单纯性UTI的疫苗方面的进展，这将显着改善复发性UTI妇女的生活质量，并使更好的抗生素管理成为可能。重要信息尿路感染（UTI）是人类最常见的细菌感染之一，在其一生中至少影响一半的妇女一次。抗生素耐药性和医疗保健成本的上升强调了开发针对最常见的UTI病原体大肠杆菌的疫苗的必要性。给小鼠鼻内接种一种解毒的不耐热肠毒素和两种表面暴露的受体Hma或lutA，显著降低了膀胱中的细菌负荷。这项工作突出了UTI疫苗开发的进展，该疫苗采用适合人类使用的佐剂和编码铁限制性尿路感染所需的外膜铁受体的抗原配制。
Urinary tract infections (UTI) affect half of all women at least once during their lifetime. The rise in the numbers of extended-spectrum beta-lactamase-producing strains and the potential for carbapenem resistance within uropathogenic Escherichia coli (UPEC), the most common causative agent of UTI, create an urgent need for vaccine development. Intranasal immunization of mice with UPEC outer membrane iron receptors FyuA, Hma, IreA, and lutA, conjugated to cholera toxin, provides protection in the bladder or kidneys under conditions of challenge with UPEC strain CFT073 or strain 536. On the basis of these data, we sought to optimize the vaccination route (intramuscular, intranasal, or subcutaneous) in combination with adjuvants suitable for human use, including aluminum hydroxide gel (alum), monophosphoryl lipid A (MPLA), unmethylated CpG synthetic oligodeoxynucleotides (CpG), polyinosinic:polycytidylic acid (polyIC), and mutated heat-labile E. coil enterotoxin (dmLT). Mice intranasally vaccinated with dmLT-lutA and dmLT-Hma displayed significant reductions in bladder colonization (86-fold and 32-fold, respectively), with 40% to 42% of mice having no detectable CFU. Intranasal vaccination of mice with CpG-lutA and polyIC-lutA significantly reduced kidney colonization (131-fold) and urine CFU (22-fold), respectively. dmLT generated the most consistently robust antibody response in intranasally immunized mice, while MPLA and alum produced greater concentrations of antigen-specific serum IgG with intramuscular immunization. On the basis of these results, we conclude that intranasal administration of Hma or lutA formulated with dmLT adjuvant provides the greatest protection from UPEC UTI. This report advances our progress toward a vaccine against uncomplicated UTI, which will significantly improve the quality of life for women burdened by recurrent UTI and enable better antibiotic stewardship.IMPORTANCE Urinary tract infections (UTI) are among the most common bacterial infection in humans, affecting half of all women at least once during their lifetimes. The rise in antibiotic resistance and health care costs emphasizes the need to develop a vaccine against the most common UTI pathogen, Escherichia coli. Vaccinating mice intranasally with a detoxified heat-labile enterotoxin and two surface-exposed receptors, Hma or lutA, significantly reduced bacterial burden in the bladder. This work highlights progress in the development of a UTI vaccine formulated with adjuvants suitable for human use and antigens that encode outer membrane iron receptors required for infection in the iron-limited urinary tract.