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.

膀胱是感染的常见部位，约 50% 的 18-50 岁女性至少有一次尿道感染。 尿路感染 (UTI) 和约 40% 的医院获得性院内感染是导尿管后的尿路感染 介绍。大多数尿路感染是由尿路致病性大肠杆菌 (UPEC) 引起，首先是膀胱定植，然后 然后提升到肾脏。在肾盂肾炎严重的情况下，细菌可以进入血液 - 引起菌血症、败血症（尿脓毒症）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。用于的主要体内哺乳动物模型 生物医学研究对象是老鼠。然而，环境微生物暴露是一个重要的区别 使用小鼠模型进行实验时必须考虑基本人类生物学和实验室小鼠生物学之间的差异 评估免疫系统的健康状况。人类自然会接触共生菌和致病菌 微生物从出生起就存在，而成年人的免疫系统因此受到每个人的训练 遇到。相比之下，实验室小鼠通常被饲养在特定的无病原体 (SPF) 条件下。尽管 SPF 外壳是提高实验重现性的关键，同时也进一步拉开了距离 小鼠模型源自人类，很大程度上是因为 SPF 小鼠在生活中接触的微生物有限。 该提案利用了一种新颖的小鼠模型，该模型模仿了人类生物学的一个关键方面——暴露于 多种持续和已解决的感染可以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，经历过微生物污染的老鼠成熟的免疫系统会 局部 UPEC 感染和加速 UTI 后，膀胱中会产生更强大的免疫反应 清除，但全身性尿脓毒症期间炎症反应加剧并增加死亡率。 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、成人样免疫系统 生理微生物暴露）会影响局部和全身 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有价值的新信息基础 关于尿路感染和尿脓毒症引起的免疫反应和病理生理学。最终得到的数据 拟议的研究对于理解尿路感染具有很大的意义。需要强调的是 我们的“脏”小鼠模型旨在成为 SPF 小鼠的新补充，而不是替代品 通常用于研究，并作为发现新的有效疗法的宝贵工具 对生理微生物暴露引起的独特环境扰动敏感。