Novel Vaccines To Evoke Bladder Mucosal Immunity

激发膀胱粘膜免疫的新型疫苗

• 批准号: 7714327
• 负责人: David J Klumpp
• 金额: $ 22.88万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714327
• 关键词: Adoptive Transfer; Antibodies; Attenuated; Attenuated Vaccines; Bacteria; Bladder; CD8-Positive T-Lymphocytes; CD8B1 gene; Catheters; Cells; Cellular Immunity; Communicable Diseases; Data; Genes; Healthcare Systems; High Prevalence; Homologous Gene; Immune response; Immunity; Immunization; Infection; Infection prevention; Kidney; Klebsiella; Klebsiella pneumonia bacterium; Knock-out; Ligase; MHC Class I Genes; Mediating; Mirabilis; Modeling; Morbidity - disease rate; Mucosal Immunity; Mus; Mutation; O Antigens; Patients; Phenotype; Predisposition; Process; Proteus; Proteus mirabilis; Pseudomonas; Pseudomonas aeruginosa; Recurrence; Role; Route; Site; T-Lymphocyte; Testing; Urinary tract; Urinary tract infection; Uropathogenic E. coli; Urothelial Cell; Vaccination; Vaccines; Woman; base; community-acquired UTI; economic impact; man; men; mucosal site; mutant; novel; novel vaccines; pathogen; pathogenic bacteria; response; urinary; vaccine candidate; vaccine development

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.

描述（由申请人提供）：尿路感染（UTI）是第二常见的传染病，并引起严重的患者发病率和经济影响。大约一半的女性将在其一生中遭受UTI的痛苦，其中约25％会遭受反复发作的UTI（RUTI），这表明患者之间的宿主敏感性差异。肝病大肠杆菌（UPEC）大约导致90％的社区获得的UTI，但多种细菌（如Proteus mirabilis，pseudomonas铜绿假单胞菌和肺炎克雷伯氏菌）通常与复杂的UTI有关。由于现在已知UPEC和其他细菌在小鼠和男性的膀胱叶状细胞内建立稳定的细胞内储层，因此新兴的范式是这种细胞内细菌储层是ruti的基础。膀胱中的适应性免疫知之甚少，事实证明，以前对尿路疫苗的尝试略有成功。我们最近开发了一种鼠重新感染的UTI感染模型，以表征对UPEC的免疫反应，基于对典型的UPEC分离株NU14的感染，该模型通过导管引入了小鼠的膀胱腔内。使用该模型，我们证明T细胞和抗体都介导了针对NU14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NU14突变体，该突变体高度减弱，以感染尿路。初步研究表明，该NU14突变体对膀胱和肾脏均赋予对随后在野生型NU14或系统发育范围内的UPEC菌株的挑战，并提出增强的能力来消除细胞内UPEC储层。因此，我们假设致病细菌的WAAL突变代表了通过引起能够消除细胞内储层的增强细胞介导的反应来保护膀胱免受ruti的新疫苗。为了检验这一假设，我们将追求三个目标。在AIM 1中，我们将确定由Nu14-？Waal诱导的保护性免疫的组成部分。在AIM 2中，我们将确认WAAL疫苗对复杂的UTI病原体，克雷伯菌和假单胞菌的普遍性。在AIM 3中，我们将量化通过静脉外部位的WAAL疫苗引起的免疫反应。因此，我们的研究既对RFA都有很高的反应，又为新型疫苗预防UTI铺平了道路。美国数以百万计的患者遭受尿路感染，导致医疗系统的发病率明显和负担。尽管感染的患病率很高，但对膀胱免疫反应的了解鲜为人知，并且没有有效的疫苗来防止感染。该项目将表征对新型疫苗的免疫反应，以治疗尿路感染。