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.

项目概要 发育过程中的微生物定植会影响微生物组的组装、免疫系统功能和 晚年的健康结果。该提议的中心假设是免疫平衡是 在免疫系统的早期发育和教育中建立的免疫系统可能会因滞后现象而产生偏差 以前的宿主遇到过微生物。接触的时间和顺序（即微生物暴露 优先效应）可能会耐受或促进宿主免疫反应。一种新型的无菌生物（但不是无菌的/细菌的） 免费）模型宿主非洲爪蛙（Xenopus laevis）是探测关键窗口和兴奋剂的理想选择 免疫系统的发育。我们在这项免疫教育研究中引用了克罗格原理 两栖动物的系统，因为“对于大量的问题，会选择一些动物，或者一些动物 这样的动物，可以最方便地对其进行研究”（Krogh 1929，美国生理学杂志）。 青蛙的早期发育操作比小鼠更容易，并且青蛙的免疫调节模式 两栖动物，如小鼠和其他脊椎动物，与人类的反应类似。两栖动物也是理想的选择 用于研究由于更宽松的体温和清晰的环境而在人类中出现的真菌感染 生存读数。具体目标是：（1）镰刀菌感染的免疫滞后效应和 (2) - 对微生物组的免疫滞后效应。在目标 1 中，我们将建立发展 通过微生物暴露进行免疫教育的窗口。然后我们将比较活微生物的刺激，包括 个体病原体、共生体或高度多样性的自然群落，以及微生物相关分子 模式（MAMP）和宿主损伤信号。我们将观察新发或重复的疾病结果 暴露于在发育高峰阶段施用的临床剂量的镰孢菌并量化免疫基因 转录反应。因此，我们将测试免疫滞后使宿主耐受的因素 使宿主对真菌病原体无反应或引发反应。这一目标将进一步 建立非洲爪蟾发育和免疫学模型系统以及新兴真菌病原体 人类并提供了一种创新方法来表明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 宿主微生物组的组合，并测量微生物伙伴对病原体的潜在直接影响 在培养物中确定这些共生体是否被免疫滞后促进或抑制。这个目标 将在基于课程的本科生中从事高年级本科生（实习生）的培训 研究经验（CURE）。这些目标将通过利用爪蟾知生系统来实现， 镰刀菌感染模型、定制 NanoString 免疫基因面板以及将本科生纳入 使用 CURE 进行研究。合作研究团队拥有最先进的设施和跨学科的 涵盖比较免疫学、微生物组和传染性病原体的专业知识。