Novel Vaccines To Evoke Bladder Mucosal Immunity

描述（由申请方提供）：尿路感染（UTI）是第二常见的传染病，可导致严重的患者发病率和经济影响。大约一半的女性在其一生中会遭受UTI，其中约25%会遭受复发性UTI（鲁蒂），这表明患者之间的宿主易感性存在差异。肾盂肾炎大肠大肠杆菌（UPEC）引起大约90%的社区获得性UTI，但是多种细菌如奇异变形杆菌、铜绿假单胞菌和肺炎克雷伯菌通常与复杂性UTI相关。由于现在已知UPEC和其他细菌在小鼠和人的膀胱尿路上皮细胞内建立稳定的细胞内储库，因此一个新兴的范例是这种细胞内细菌储库是鲁蒂的基础。对膀胱中的适应性免疫知之甚少，并且先前对UTI疫苗的尝试已被证明是勉强成功的。我们最近开发了一种UTI的小鼠再感染模型，以表征对UPEC的免疫应答，该模型基于通过导管引入小鼠膀胱腔的原型UPEC分离株NU 14的感染。使用该模型，我们证明了T细胞和抗体都介导针对NU 14感染的保护性免疫。在平行研究中，我们还鉴定了waaL基因中的NU 14突变体，其对于尿路感染是高度减毒的。初步研究表明，该NU 14突变体赋予膀胱和肾脏针对随后的野生型NU 14或遗传多样性UPEC菌株的攻击的显著保护，并表明增强的根除细胞内UPEC储库的能力。因此，我们假设致病菌的waaL突变代表了通过引发能够消除细胞内储库的增强的细胞介导的应答来保护膀胱免受鲁蒂的新型疫苗。为了验证这一假设，我们将追求三个目标。在目的1，我们将确定NU 14-？哇。在目标2中，我们将确认waaL疫苗对复杂UTI病原体变形杆菌属、克雷伯氏菌属和假单胞菌属的普遍性。在目标3中，我们将量化通过在尿外部位施用waaL疫苗诱导的免疫应答。因此，我们的研究对RFA具有高度反应性，并为新型疫苗预防UTI铺平了道路。在美国，数百万患者患有尿路感染，导致显著的发病率和医疗保健系统的负担。尽管感染率很高，但对膀胱免疫反应知之甚少，也没有有效的疫苗来预防感染。该项目将描述对一类新型疫苗的免疫反应，以治疗尿路感染。

DESCRIPTION (provided by applicant): Urinary tract infection (UTI) is the second most common infectious disease and causes significant patient morbidity and economic impact. Approximately half of all women will suffer a UTI during their lifetime, and about 25% of those will suffer recurrent UTIs (rUTI), suggesting differences in host susceptibility between patients. Uropathogenic E. coli (UPEC) cause approximately 90% of community-acquired UTIs, but diverse bacteria such as Proteus mirabilis, Pseudomonas aeruginosa, and Klebsiella pneumoniae are often associated with complicated UTIs. Since UPEC and other bacteria are now known to establish stable intracellular reservoirs within bladder uroepithelial cells in mice and men, an emerging paradigm is that such intracellular bacterial reservoirs underlie rUTI. Little is known of adaptive immunity in the bladder, and previous attempts at vaccines for UTI have proven marginally successful. We recently developed a murine re-infection model of UTI to characterize immune responses to UPEC, based on infection with the prototypical UPEC isolate NU14 that is introduced into the bladder lumen of mice via catheter. Using this model, we demonstrated that both T cells and antibodies mediate protective immunity against NU14 infection. In parallel studies, we also identified an NU14 mutant in the waaL gene that is highly attenuated for infection of the urinary tract. Preliminary studies demonstrate that this NU14 mutant confers significant protection of both the bladder and kidneys against subsequent challenge with either wild type NU14 or phylogenetically diverse UPEC strains and suggest an enhanced capacity to eradicate intracellular UPEC reservoirs. Therefore, we hypothesize that waaL mutations of pathogenic bacteria represent novel vaccines for protecting the bladder from rUTI by eliciting enhanced cell-mediated responses capable of eliminating intracellular reservoirs. To test this hypothesis, we will pursue three aims. In Aim 1, we will determine components of protective immunity induced by NU14-?waaL. In Aim 2, we will confirm the generalizability of waaL vaccines to the complicated UTI pathogens Proteus, Klebsiella, and Pseudomonas. In Aim 3, we will quantify immune responses induced by administration of waaL vaccines at extra-urinary sites. Thus, our study is both highly responsive to the RFA and paves the way for novel vaccines to protect against UTI. Millions of patients in the U.S. suffer urinary tract infection, causing significant morbidity and burden on the healthcare system. Despite the high prevalence of infection, little is known about the bladder immune response, and no effective vaccines exist to prevent infection. This project will characterize immune responses to a novel class of vaccines to treat urinary tract infection.