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

利用微生物暴露研究对尿路致病性大肠杆菌的免疫反应

• 批准号: 10237569
• 负责人: Thomas S Griffith
• 金额: $ 23.24万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237569
• 关键词: Adult; Affect; Bacteremia; Bacteria; Biology; Biomedical Research; Birth; Bladder; Bladder Diseases; Blood Circulation; Catheters; Cells; Cessation of life; Clinical; Clinical Research; Communicable Diseases; Complement; Data; Development; Escherichia coli; Escherichia coli Infections; Exhibits; Experimental Models; Exposure to; Foundations; Functional disorder; Generations; Global Change; Goals; Hospitals; Housing; Human; Human Biology; Immune; Immune response; Immune system; Infection; Infection prevention; Inflammatory Response; Kidney; Knowledge; Laboratory mice; Lung; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Organ; Pathology; Physiological; Predisposition; Pyelonephritis; Recurrence; Reproducibility; Research; Sepsis; Site; Skin; Systemic infection; Testing; Training; Translating; Urinary tract infection; Uropathogenic E. coli; Woman; Work; aged; clinically relevant; commensal microbes; efficacious treatment; emerging pathogen; experience; experimental study; fitness; germ free condition; immune function; in vivo; intravesical; microbial; mortality; mouse model; neonatal human; neonate; nosocomial UTI; novel; pathogenic microbe; polymicrobial sepsis; pre-clinical; prevent; recurrent infection; response; tool; treatment response; urinary

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.

膀胱是常见的感染部位，因为大约50%的18-50岁女性至少会有一个尿路 尿路感染(UTI)和约40%的医院获得性感染是尿管后的UTI 引言。大多数尿路感染是由尿路致病性大肠杆菌(UPEC)引起的，首先是膀胱定植和 然后提升到肾脏。在严重的肾盂肾炎病例中，细菌可以进入血液- 导致菌血症、败血症(尿毒症)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。主要的活体哺乳动物模型用于 生物医学研究是一只老鼠。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小鼠生物学之间的关系 评估免疫系统的适合性。人类自然地接触到共生和致病 微生物从出生起，成年人类的免疫系统因此变得由每个 相遇。相比之下，实验室小鼠通常被关在特定的无病原体(SPF)条件下。而当 SPF外壳是提高实验重复性的关键，它同时也进一步延长了距离 小鼠模型来自人类，很大程度上是因为SPF小鼠生活在有限的微生物暴露下。 这一建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 多个持续和已解决的感染训练免疫系统对新病原体做出强有力的反应。 我们的中心假设认为，在经历过微生物的脏鼠中，成熟的免疫系统将 在局部UPEC感染和加速UTI后，膀胱内有更强的免疫反应 清除，但在全身性尿毒症期间，炎症反应夸大，死亡率增加。 这个项目的总体目标是研究如何改变免疫系统的“起点”(即，幼稚， SPF小鼠的新生免疫系统与“脏”小鼠的成熟成体免疫系统 生理性微生物暴露)影响局部和全身UPEC感染的免疫反应。我们的 对“脏”老鼠进行研究的理由是，我们将积累一个有价值的新信息基础 关于尿路感染和尿毒症引起的免疫反应和病理生理学。最终，获得的数据 来自拟议的研究将对了解尿路感染有很大的相关性。重要的是要强调 我们的“脏”小鼠模型旨在成为SPF小鼠的新补充，而不是替代。 通常用于研究，并作为发现新的有效疗法的有价值的工具 对生理性微生物暴露引起的独特环境扰动敏感。