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: 10413143
• 负责人: Thomas S Griffith
• 金额: $ 19.38万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413143
• 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; Persons; 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.

膀胱通常是感染的部位，因为约50％的18-50岁女性将至少有一个尿 道感染（UTI）和约40％的医院获得的医院感染是尿导管后的UTI 介绍。大多数尿路斯是由尿道病大肠杆菌（UPEC）引起的，从膀胱定殖和 然后向孩子们提升。在严重的肾上腺炎病例中，细菌可以进入血液 - 引起细菌，败血症（尿素）和死亡。重要的是，免疫系统参与 这些病理的发展和对治疗的反应。用于体内哺乳动物模型 生物医学研究是小鼠。但是，环境微生物暴露是重要的差异 在使用鼠标模型时必须考虑的基本人类和实验室小鼠生物学之间 评估免疫系统的适应性。人类自然暴露于共生和致病性 从出生开始的微生物，以及成年人类的免疫系统，因此受到每个人的训练 遇到。相比之下，实验室小鼠通常被安置在特定的无病原体（SPF）条件下。尽管 SPF外壳对于提高实验可重现性一直是关键，它已经进一步远距离 来自人类的小鼠模型很大程度上是因为SPF小鼠在微生物暴露有限的情况下过着生活。 该建议利用了一种新型的老鼠模型，该模型模仿了人类生物学的关键方面 - 暴露于 多种正在进行的和解决的感染训练免疫系统，以对新病原体的强大反应。 我们的中心假设认为，在微生物经验丰富的肮脏小鼠中成熟的免疫系统将 局部UPEC感染后，膀胱中的免疫反应更强大，并加速了UTI 清除率，但夸张的炎症反应和全身性尿中的死亡率增加。 该项目的总体目标是研究如何改变免疫系统的“起点”（即幼稚， SPF小鼠的新生儿样免疫系统与“脏”小鼠的成熟，成年免疫系统 物理微生物暴露）会影响局部和全身UPEC感染的免疫增强响应。我们的 用“脏”老鼠进行研究的理由是，我们将积累宝贵的新信息基础 最终，获得的数据 从拟议的研究中，将与理解UTI具有很大的相关性。重要的是要强调 我们的“肮脏”鼠标模型本来是一种新颖的补充，而不是替代SPF小鼠 通常用于研究 对物理微生物暴露引起的独特环境扰动敏感。