UTI Immune Modulation by LPS Structure

描述(由申请人提供)：尿路感染(UTI)是第二种最常见的细菌感染，并导致显著的患者发病率。一半的女性在一生中将遭受至少一次尿路感染，而其中25%的女性将遭受反复感染。尿路致病性大肠埃希菌(UPEC)是最常见的尿路感染病原体，耐药菌株的比例正在迅速增加，因此需要一种疫苗来预防尿路感染的复发。UPEC以细胞外病原体的形式存在，形成不能用抗生素治疗的细胞内储存库。我们的研究将开发一种减毒活疫苗。最理想的复发性UTI疫苗将1)诱导针对目标管腔细菌的抗体反应，2)促进针对细胞内UPEC储存库的细胞中介反应，3)产生强烈的记忆反应。初步数据显示，UPEC在感染时会诱导默认的体液反应，使细胞内的储存物留在膀胱内，并导致复发 感染。UPEC脂多糖(LPS)可触发和调节先天免疫反应，但其在获得性免疫反应中的作用尚不清楚。UPEC的突变与改变的内毒素接种UPEC的挑战，并部分根除UPEC储存库，提示增强的细胞介导性反应。众所周知，是抗原提呈启动和扭曲T细胞反应，因此我们假设其他的内毒素结构突变在抗原提呈水平上调节先天反应，从而可以倾斜获得性免疫反应，优化疫苗的性质。我们将通过对脂多糖结构基序的系统询问来解决这一假说，并从APC功能、T细胞偏斜和疫苗效力的水平表征对UPEC突变的关键先天和获得性免疫反应。这些研究将增加我们对UPEC发病机制的理解，并为尿路感染的新型候选疫苗提供关键的临床前数据。

DESCRIPTION (provided by applicant): Urinary tract infections (UTIs) are the second most common bacterial infection and cause significant patient morbidity. Half of all women will suffer from at least one UTI during her lifetime, while 25% of these women will endure recurrent infections. Uropathogenic E. coli (UPEC) are the most common uropathogen, and the rate of antibiotic resistant strains is increasing rapidly, thus escalating the need for a vaccine to prevet recurrence of UTIs. UPEC exist as extracellular pathogens and form intracellular reservoirs that cannot be treated by antibiotics. Our studies will develop a live-attenuated vaccine. The optimal recurrent UTI vaccine would 1) elicit an antibody response to target lumenal bacteria, 2) promote cell mediated responses to target intracellular UPEC reservoirs and 3) produce a strong memory response. Preliminary data show UPEC induces a default humoral response upon infection that allows intracellular reservoirs to remain in the bladder and leads to recurrent infections. UPEC lipopolysaccharide (LPS) triggers and modulates innate immune responses, although its role in adaptive immune response is understudied. A mutant of UPEC with altered LPS vaccinates against UPEC challenges, and partially eradicates UPEC reservoirs, suggesting enhanced cell-mediated responses. It is well-known antigen presentation initiates and skews T cell responses, therefore we hypothesize other mutations of LPS structure modulate innate responses at the level of antigen presentation, thus can skew the adaptive immune responses and optimize vaccine properties. We will address this hypothesis through a systematic interrogation of LPS structural motifs and characterize key innate and adaptive immune responses to UPEC mutant at the level of APC function, T cell skewing and vaccine efficacy. These studies will increase our understanding of UPEC pathogenesis and provide critical pre-clinical data on novel vaccine candidates for urinary tract infections.