Exploiting microbial exposure to study the immune response to uropathogenic E. coli

膀胱是一个常见的感染部位，因为约50%的18 - 50岁的女性至少会有一个泌尿道感染。 尿路感染（UTI）和~40%的医院获得性医院感染是导尿管后的UTI 导论.大多数尿路感染是由尿路致病性大肠杆菌引起的。大肠杆菌（UPEC），从膀胱定植开始， 然后上升到肾脏在严重的肾盂肾炎病例中，细菌可以进入血液- 引起菌血症、败血症（尿败血症）和死亡。重要的是，免疫系统参与了 这些病理的发展和对治疗的反应。用于研究的主要体内哺乳动物模型 生物医学研究是老鼠。然而，环境微生物暴露是一个重要的区别 在使用小鼠模型时必须考虑的基本人类和实验室小鼠生物学之间的差异， 评估免疫系统的适应性。人类自然会接触到有毒和致病的 从出生开始，人类的免疫系统就受到每一种微生物的训练， 遭遇相比之下，实验室小鼠通常在无特定病原体（SPF）条件下饲养。而 SPF住房一直是提高实验重现性的关键，同时也进一步拉开了距离。 从人类的小鼠模型，主要是因为SPF小鼠生活在有限的微生物暴露的生活。 这项提议利用了一种新的小鼠模型，该模型模拟了人类生物学的一个关键方面-暴露于 多重进行中的和已解决的感染训练免疫系统对新病原体作出强有力的反应。 我们的中心假设认为，在微生物经验丰富的脏老鼠的成熟免疫系统将 在局部UPEC感染和加速UTI后， 清除，但在全身性尿脓毒症过程中，炎症反应加剧，死亡率增加。 该项目的总体目标是研究如何改变免疫系统的"起点"（即，天真， SPF小鼠的类成体免疫系统与"脏"小鼠中成熟的类成体免疫系统 生理微生物暴露）影响局部和全身UPEC感染的免疫应答。我们 用“脏”老鼠进行研究的理由是，我们将积累一个有价值的新的信息基础。 关于UTI和尿脓毒症诱导的免疫反应和病理生理学。最终，获得的数据 从拟议的研究将是非常相关的了解尿路感染。必须强调 我们的“脏”小鼠模型是对SPF小鼠的一种新的补充，而不是替代 通常用于研究，并作为一个有价值的工具，以发现新的有效的疗法，可能是 对生理微生物暴露导致的独特环境扰动敏感。

The bladder is a frequent site of infection, as ~50% of women aged 18-50 years will have at least one urinary tract infection (UTI) and ~40% of hospital-acquired nosocomial infections are UTIs after urinary catheter introduction. Most UTIs are caused by uropathogeneic E. coli (UPEC), starting with bladder colonization and then ascension to the kidneys. In severe cases of pyelonephritis, the bacteria can enter the bloodstream – causing bacteremia, sepsis (urosepsis), and death. Importantly, the immune system is involved in the development of these pathologies and response to treatment. The dominant in vivo mammalian model used in biomedical research is the mouse. However, environmental microbial exposure is an important difference between basic human and laboratory mouse biology that must be considered when using mouse models to evaluate the fitness of the immune system. Humans are naturally exposed to commensal and pathogenic microbes from birth, and the immune system of adult humans consequently becomes trained by each encounter. In contrast, laboratory mice are often housed under specific pathogen-free (SPF) conditions. While SPF housing has been key in increasing experimental reproducibility, it has simultaneously further distanced the mouse model from humans, largely because SPF mice live their lives with limited microbial exposure. This proposal leverages a novel mouse model that mimics a critical aspect of human biology – exposure to multiple ongoing and resolved infections trains the immune system for robust responses to new pathogens. Our central hypothesis holds that the matured immune system in microbially-experienced dirty mice will respond with a more robust immune response in the bladder after local UPEC infection and accelerated UTI clearance, but an exaggerated inflammatory response and increased mortality during systemic urosepsis. The overall goal of this project is to study how changing the “starting point” of the immune system (i.e., naïve, neonate-like immune system of SPF mice vs. mature, adult-like immune system in ‘dirty’ mice after physiological microbial exposure) affects the immune response local and systemic UPEC infections. Our rationale for the studies with ‘dirty’ mice is that we will amass a valuable new foundation of information regarding UTI and urosepsis-induced immune responses and pathophysiology. Ultimately, the data obtained from the proposed studies will be of great relevance to the understanding UTIs. It is important to emphasize our ‘dirty’ mouse model is meant to be a novel complement to, rather than a replacement of, the SPF mice typically used in research, and serve as a valuable tool to discover new efficacious therapies that may be sensitive to unique environmental perturbations resulting from physiological microbial exposure.