Mucosal Immune Checkpoints in Chronic Bacterial Cystitis

描述(由申请人提供)：在这份申请中，我请求职业发展奖支持，以调查“慢性细菌性膀胱炎的粘膜免疫检查点”。我将与我的共同导师马尔科·科隆纳和斯科特·胡尔特格伦合作开展这项工作，他们都在华盛顿大学。这些免疫学和微生物学领域的专家的结合将成为一个伟大的指导团队，因为我开始了这个联合的博士后奖学金。这项合作源于我对慢性细菌性膀胱炎小鼠模型的兴趣。尿路感染(UTI)很常见，费用很高，而且经常反复发作。UPEC是尿路感染最常见的病原菌。UPEC诱导宿主防御以回应殖民。了解宿主反应在这种疾病中的作用对于我们开发有效的疫苗和治疗方法至关重要。我们发现，幼年C3H/HEN小鼠对UPEC感染有两种截然不同的反应：要么在2周内消除感染，要么发展成持续至少7个月的慢性膀胱炎。此外，慢性膀胱炎的发展与明显更严重的急性宿主反应密切相关。这种过敏样反应在其他被研究的小鼠品系中没有看到，它构成了本研究假设的基础，即在慢性膀胱炎发生之前有一个宿主检查点被触发。这项研究将通过研究这一检查点的细胞和分子机制并检验因果关系来检验这一假说。当我回答这些难题时，科隆纳博士将在这个项目中提供指导、知识和技术专长。Hultgren博士将在传染病研究和UTI小鼠模型领域提供指导和专业知识。华盛顿大学是从事科学研究的绝佳场所，拥有众多支持和核心设施。2003年离开临床兽医行业后，我开始跟随Hultgren博士进行博士培训，并于2008年8月获得微生物学博士学位。在我的研究生工作接近尾声时，我对宿主对感染的反应产生了兴趣，并决定攻读免疫学博士后奖学金，以拓宽我在传染病机制方面的专业知识。我希望在一家学术研究机构工作，作为一名独立研究员研究宿主与病原体的相互作用。相关性(见说明书)：尿路感染(UTI)是一个主要问题：它们很常见，费用很高，而且经常是复发或慢性的。我们已经建立了一种慢性尿路感染的小鼠模型，感染的细菌是尿路致病的大肠杆菌，并发现慢性感染的发展与感染早期的类过敏膀胱反应有关。在发生这种反应后，这些小鼠容易复发尿路感染，这为人类复发的尿路感染提供了可能的解释。

DESCRIPTION (provided by applicant): In this application, I am requesting career development award support to investigate "Mucosal Immune Checkpoints in Chronic Bacterial Cystitis." I will be undertaking this work in collaboration with my co-mentors, Marco Colonna and Scott Hultgren, both here at Washington University. This marriage of these experts in the fields of Immunology and Microbiology will serve as a great mentoring team as I embark on this joint post- doctoral fellowship. This collaboration arose out of my interest in a murine model of chronic bacterial cystitis. Urinary tract infections (UTI) are common, costly, and very often recurrent. Uropathogenic E. coli (UPEC) are the most common cause of UTI. UPEC elicit host defenses in response to colonization. Understanding the role of the host response in this disease is critical for our ability to develop effective vaccines and therapeutics. We have found that juvenile C3H/HeN mice have two distinct responses to UPEC infection: either they resolve infection within 2 weeks or they develop chronic cystitis that lasts for at least 7 months. Furthermore, development of chronic cystitis strongly correlates with a significantly more severe acute host response. This allergic-like response, which is not seen in other mouse strains studied, forms the basis for the hypothesis of this study, which is that there is a host checkpoint that is being triggered prior to the development of chronic cystitis. This study will test this hypothesis by investigate the cellular and molecular mechanism of this checkpoint and testing for causality. Dr. Colonna will be providing mentorship, knowledge and technical expertise during this project as I address these difficult questions. Dr. Hultgren will be providing mentorship and expertise in the field of infectious disease research and the murine model of UTI. Washington University is a wonderful place to pursue scientific research, with numerous support and core facilities. Upon leaving clinical veterinary practice in 2003, I began my doctoral training with Dr. Hultgren and graduated with a Ph.D. in Microbiology in August, 2008. I became interested in host responses to infection towards the end of my graduate work and decided to pursue a post-doctoral fellowship in Immunology to broaden my expertise in mechanisms of infectious disease. I hope to work at an academic research institution as an independent investigator studying the host-pathogen interaction. RELEVANCE (See instructions): Urinary tract infections (UTI) are a major problem: they are common, costly, and often recurrent or chronic. We have developed a mouse model of chronic urinary tract infection with the bacterium uropathogenic E. coli, and found that development of chronic infection is associated with an allergic-like bladder response early in infection. After having this reaction, these mice are prone to recurrent UTI, providing a possible explanation for recurrent UTI in humans.