Mucosal Immune Checkpoints in Chronic Bacterial Cystitis

描述（由申请人提供）：在此申请中，我请求职业发展奖支持，以调查“慢性细菌性膀胱炎的粘液免疫检查点”。“我将与我的共同导师，马可科隆纳和斯科特胡尔特格伦，都在这里在华盛顿大学合作开展这项工作。这些免疫学和微生物学领域的专家的婚姻将成为一个伟大的指导团队，因为我走上了这个联合博士后奖学金。这次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）是常见的，昂贵的，而且经常复发。肾盂肾炎大肠大肠杆菌（UPEC）是UTI最常见的原因。UPEC引发宿主防御以响应定殖。了解宿主反应在这种疾病中的作用对于我们开发有效疫苗和治疗方法的能力至关重要。我们发现幼年C3 H/HeN小鼠对UPEC感染有两种不同的反应：要么在2周内解决感染，要么发展为持续至少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。这种过敏样反应在研究的其他小鼠品系中未观察到，形成了本研究假设的基础，即在慢性膀胱炎发展之前触发了宿主检查点。本研究将通过研究该检查点的细胞和分子机制并检验因果关系来验证这一假设。科隆纳博士将提供指导，知识和技术专长，在这个项目，因为我解决这些困难的问题。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。华盛顿大学是一个追求科学研究的好地方，拥有众多的支持和核心设施。在2003年离开临床兽医实践后，我开始了与Hultgren博士的博士培训，并以博士学位毕业。微生物学2008年8月在我的研究生工作即将结束时，我开始对宿主对感染的反应感兴趣，并决定攻读免疫学博士后研究金，以扩大我在传染病机制方面的专业知识。我希望在一个学术研究机构工作，作为一个独立的研究人员研究宿主-病原体相互作用。相关性（见说明书）：尿路感染（UTI）是一个主要问题：它们很常见，昂贵，而且经常复发或慢性。我们建立了一种慢性尿路感染的小鼠模型。大肠杆菌，并发现慢性感染的发展与感染早期的过敏样膀胱反应有关。在有这种反应后，这些小鼠容易复发UTI，这为人类复发UTI提供了一个可能的解释。

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.