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 微生物在发育过程中的定植影响微生物组的组装、免疫系统的功能和 晚年的健康状况。这一提议的中心假设是免疫平衡是 建立在早期发展和教育中的免疫系统可能会受到滞后的影响 以前的宿主与微生物相遇。相遇的时间和顺序(即接触微生物 优先效应)可耐受或促进宿主免疫应答。一种新的灵知菌(但不是无菌/细菌- 自由)模型宿主，非洲爪蛙，非洲爪蛙，是探测关键窗口和兴奋剂的理想选择 免疫系统发育的关键因素。我们引用克罗的原理来研究免疫教育 系统在两栖动物，因为“对于大量的问题，会有一些动物的选择，或几个 这样的动物，可以在上面最方便地研究它“(Krogh 1929，《美国生理学杂志》)。 青蛙的早期发育操作比老鼠更容易，免疫调节模式在青蛙中 两栖动物，如老鼠和其他脊椎动物，类似于人类的反应。两栖动物也是理想的选择 用于研究由于更允许的体温和更透明的环境而出现的人类真菌感染 生存读数。其具体目的是：(1)镰刀菌感染的免疫滞后效应和 (2)--微生物组的免疫滞后效应。在目标1中，我们将建立发展性 微生物暴露免疫教育窗口。然后我们将比较活微生物的刺激作用，包括 单个病原体、互助者或高度多样性的自然群落，以及与微生物相关的分子 模式(MAMP)和主机损坏信号。我们将根据新的或重复的情况观察疾病结果 临床剂量赤霉菌在发育高峰阶段的暴露及免疫基因的定量 转录反应。因此，我们将测试免疫滞后对宿主耐受的因素 无反应或激发宿主对真菌病原体的反应。这一目标将进一步 建立非洲爪哇发育和免疫学模型系统以及新出现的真菌病原体 并提供了一种创新的方法来指示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小鼠的影响。 宿主微生物群的组装，并测量微生物伙伴对病原体的潜在直接影响 以确定免疫滞后是促进还是抑制这些共生体。这一目标 将从事以课程为基础的本科高级本科生(实习生)的培养 研究经验(治愈)。这些目标将通过利用非洲爪哇灵知生菌系统来实现， 镰刀菌感染模型，定制纳米链免疫基因小组，并纳入本科生培训 利用解药进行研究。合作研究团队拥有最先进的设施和跨学科 专业知识横跨比较免疫学、微生物群和传染病病原体。