UTI Immune Modulation by LPS Structure

描述（由申请人提供）：尿路感染（uti）是第二常见的细菌感染，并导致显著的患者发病率。所有妇女中有一半在其一生中至少遭受一次尿路感染，而其中25%的妇女将遭受反复感染。尿路致病性大肠杆菌（UPEC）是最常见的尿路病原体，抗生素耐药菌株的比例正在迅速增加，因此对预防尿路感染复发的疫苗的需求不断增加。UPEC作为细胞外病原体存在，并形成细胞内储存库，不能用抗生素治疗。我们的研究将开发出减毒活疫苗。最佳的复发性尿路感染疫苗将：1)引发针对目标肠道细菌的抗体应答；2)促进细胞介导的针对目标细胞内UPEC储存库的应答；3)产生强烈的记忆应答。初步数据显示，UPEC在感染时诱导默认的体液反应，使细胞内储存库保留在膀胱中并导致复发

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.