UTI Immune Modulation by LPS Structure

描述（由申请方提供）：尿路感染（UTI）是第二常见的细菌感染，可导致患者严重发病。一半的女性在一生中至少会遭受一次UTI，而这些女性中有25%会遭受复发性感染。肾盂肾炎大肠大肠杆菌（UPEC）是最常见的泌尿道病原体，并且抗生素耐药菌株的比率正在迅速增加，从而增加了对疫苗的需求以防止UTI的复发。UPEC作为细胞外病原体存在，并形成不能被抗生素治疗的细胞内储库。我们的研究将开发一种减毒活疫苗。最佳复发性UTI疫苗将1）引发针对靶腔内细菌的抗体应答，2）促进细胞介导的针对靶细胞内UPEC储库的应答，以及3）产生强记忆应答。初步数据显示，UPEC在感染后诱导默认体液反应，允许细胞内储库保留在膀胱中，并导致复发性膀胱炎。 感染. UPEC脂多糖（LPS）触发和调节先天性免疫反应，但其在适应性免疫反应中的作用尚未得到充分研究。具有改变的LPS的UPEC突变体针对UPEC挑战接种疫苗，并部分根除UPEC储库，表明增强的细胞介导的应答。抗原提呈是T细胞免疫应答的启动和调节机制，因此我们推测LPS结构的其他突变在抗原提呈水平上调节先天性免疫应答，从而可以调节获得性免疫应答，优化疫苗特性。我们将通过对LPS结构基序的系统询问来解决这一假设，并在APC功能、T细胞偏斜和疫苗效力的水平上表征对UPEC突变体的关键先天性和适应性免疫应答。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.