Biasing immunological development with early life microbial colonization

生命早期微生物定植导致免疫发育偏向

• 批准号: 10730933
• 负责人: DOUGLAS C WOODHAMS
• 金额: $ 44.67万
• 依托单位: UNIVERSITY OF MASSACHUSETTS BOSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-08 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730933
• 关键词: Adult; African; American; Amphibia; Animals; Autoimmune Diseases; Bacteria; Biological Assay; Biological Metamorphosis; Biological Models; Body Temperature; Chronic; Clinical; Communities; Custom; Development; Disease; Disease Outcome; Dose; Education; Educational Models; Embryo; Equilibrium; Exposure to; Fusarium; Gene Expression Regulation; Generations; Genetic Transcription; Germ-Free; Gnotobiotic; Health; Homeostasis; Human; Hypersensitivity; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Individual; Infection; Inflammatory; Investments; Irritable Bowel Syndrome; Journals; Larva; Life; Measures; Methods; Microbe; Modeling; Molecular; Mus; Mycoses; Obesity; Outcome; Pattern; Physiology; Predisposition; Preventive Medicine; Rana; Research; Research Design; Resources; Role; Signal Transduction; Specificity; Students; System; Systems Development; Testing; Time; Training; Training Programs; Vertebrates; Work; Xenopus; Xenopus laevis; biomedical scientist; comparative; equilibrium model; functional genomics; gene panel; hatching; host microbiome; host-microbe interactions; human pathogen; immune function; immune stimulant; immune system function; immunoregulation; improved; innovation; microbial; microbial colonization; microbiome; microbiota; model development; model organism; nano-string; novel; pathogen; pathogenic fungus; permissiveness; prophylactic; response; student participation; symbiont; tool; translational medicine; undergraduate research experience; undergraduate student; xenopus development

Project Summary Microbial colonization during development impacts microbiome assembly, immune system functioning, and health outcomes later in life. The central hypothesis of this proposal is that immune equilibrium is established in early development and education of the immune system can be biased by hysteresis from previous host encounters with microbes. The timing and sequence of encounter (i.e., microbial exposure priority effects) may tolerize or promote host immune responsiveness. A novel gnotobiotic (but not axenic/germ- free) model host, the African Clawed Frog, Xenopus laevis, is ideal for probing critical windows and stimulants of immune system development. We invoke Krogh’s principle for this research on education of the immune system in amphibians because “for a large number of problems there will be some animal of choice, or a few such animals, on which it can be most conveniently studied” (Krogh 1929, The American Journal of Physiology). Early developmental manipulations are easier in a frog than in a mouse, and immune regulatory patterns in amphibians, like mouse and other vertebrates, are analogous to human responses. Amphibians are also ideal for study of fungal infections emerging in humans because of more permissive body temperatures and clear survival readouts. The specific aims are: (1) Immunological Hysteresis Effects on Fusarium Infection and (2) - Immunological Hysteresis Effects on the Microbiome. In Aim 1 we will establish the developmental window for immune education by microbial exposure. We will then compare stimulation by live microbes including individual pathogens, mutualists, or high diversity natural communities, as well as microbe-associated molecular patterns (MAMPs), and host damage signals. We will observe disease outcome with respect to novel or repeat exposure to a clinical dose of Fusarium applied at a climax developmental stage and quantify immune gene transcriptional responses. We will thus test factors by which immunological hysteresis tolerizes the host toward unresponsiveness or primes the host toward responsiveness to the fungal pathogen. This aim will further establish the Xenopus model system for development and immunology as well as emerging fungal pathogens of humans and provide an innovative method for indicating potentially conserved immune gene regulation in amphibians and humans. In Aim 2 we will investigate the impacts of immunological hysteresis on the assemblage of the host microbiome, and measure the potential direct effects of microbial partners on pathogens in culture to determine whether these symbionts are facilitated or inhibited by immunological hysteresis. This aim will engage the training of advanced undergraduate students (trainees) in a Course-based Undergraduate Research Experience (CURE). The aims will be accomplished by leveraging the Xenopus gnotobiotic system, Fusarium infection model, custom NanoString immune gene panel, and inclusion of undergraduate trainees in research using the CURE. The collaborative research team has state-of-the-art facilities and interdisciplinary expertise spanning comparative immunology, the microbiome, and infectious pathogens.

项目摘要 发育过程中的微生物定植影响微生物组组装、免疫系统功能和 生活中的健康结果。这个提议的核心假设是免疫平衡是 在免疫系统的早期发展和教育中建立的免疫系统可能会受到滞后的影响， 之前宿主接触过微生物相遇的时间和顺序（即，微生物暴露 优先效应）可耐受或促进宿主免疫应答。一种新的无菌（但不是纯的/细菌- 免费）模式宿主，非洲爪蟾，非洲爪蟾，是理想的探测关键窗口和兴奋剂 免疫系统的发展。本文运用克罗格原理对免疫力教育进行了研究 两栖动物的系统，因为“对于大量的问题，将有一些动物的选择，或少数 这种动物，它可以最方便地研究”（Krogh 1929，美国生理学杂志）。 早期发育操作在青蛙中比在小鼠中容易， 两栖动物，像老鼠和其他脊椎动物一样，与人类的反应类似。两栖动物也是理想的 用于研究人类中出现的真菌感染，因为体温更宽松， 生存读数具体目的是：（1）镰刀菌感染的免疫滞后效应， (2)- 对微生物组的免疫滞后效应。在目标1中，我们将建立 通过微生物暴露进行免疫教育。然后，我们将比较活微生物的刺激，包括 个体病原体、互利共生者或高度多样性的自然群落，以及微生物相关分子 模式（MAMPs）和宿主损伤信号。我们将观察新的或重复的疾病结局 暴露于在发育高潮阶段施用临床剂量的镰刀菌，并定量免疫基因 转录反应。因此，我们将测试免疫滞后耐受宿主对 无反应或引发宿主对真菌病原体的反应。这一目标将进一步 建立非洲爪蟾模型系统，用于发育和免疫学以及新兴真菌病原体 并提供了一种创新的方法，用于指示在人类中潜在保守的免疫基因调控， 两栖动物和人类。在目标2中，我们将研究免疫滞后对免疫系统的影响。 宿主微生物组的组合，并测量微生物伴侣对病原体的潜在直接影响 以确定这些共生体是否被免疫滞后促进或抑制。这一目标 将从事高级本科生（学员）在基于课程的本科培训 研究经验（CURE）。这些目标将通过利用非洲爪蟾的知生系统来实现， 镰刀菌感染模型，自定义NanoString免疫基因面板，并将本科学员纳入 研究使用治愈。合作研究团队拥有最先进的设施和跨学科的 专业知识涵盖比较免疫学，微生物组学和传染性病原体。