Determinants of Microbiome Stability Following Pathogen Infection

病原体感染后微生物组稳定性的决定因素

• 批准号: 10712778
• 负责人: Andrea Jani
• 金额: $ 18.26万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712778
• 关键词: Acceleration; Activities of Daily Living; Affect; Antibiotics; Biological; Climate; Communicable Diseases; Communities; Containment; DNA sequencing; Development; Disease; Disease Outbreaks; Drosophila genus; Drosophila melanogaster; Ecology; Exposure to; Foundations; Future; Genes; Germ-Free; Global Change; Goals; Hawaii; Hawaiian; Health; Human; Human Microbiome; Immune response; Infection; Insecta; Knowledge; Laboratories; Lead; Link; Measures; Mentors; Metagenomics; Microbe; Modeling; Molecular; Natural experiment; Organism; Outcome; Phylogenetic Analysis; Population; Predictive Factor; Qualifying; Recurrent disease; Research; Research Project Grants; Resistance; Shotguns; Stress; Structure; System; Taxus; Temperature; Testing; Variant; Work; climate change; dietary; environmental stressor; experience; fly; human disease; improved; microbial; microbial community; microbial composition; microbiome; microbiome alteration; microbiome analysis; microbiome composition; microbiota transplantation; model organism; pathogen; pathogen exposure; pathogenic bacteria; pathogenic microbe; resilience; response; stress tolerance; success; symbiont; thermal stress; transcriptomics

PROJECT SUMMARY - Determinants of Microbiome Stability Following Pathogen Infection The human microbiome (i.e., the consortium of microbes that reside in and on the body) affects human health and development. Microbiome composition (the microbial species that are present) and diversity (the number of species) can affect microbiome function. Disturbances such as antibiotics, dietary shifts, environmental stress or pathogen infection can cause changes (perturbations) in the microbiome, which can affect microbiome function and human health. The impacts of disturbances on the microbiome and human health can be mitigated by microbiome stability, which is the microbiome’s capacity to maintain stable structure (diversity and composition) and function despite disturbances. Understanding the factors that control microbiome stability is therefore important for human health. Infectious disease and temperature stress are two disturbances of growing concern to human health due to recurring disease outbreaks and human-induced climate change. The long-term goal of the proposed research is to understand how climate and disease affect the microbiome and what factors control microbiome resistance and resilience to these disturbances. The specific aims are: (1) to determine how microbiome diversity and composition affect microbiome stability during pathogen infection; (2) to determine how long-term temperature change affects the microbiome’s response to pathogen infection. The project will leverage the model organism Drosophila melanogaster for its tractability and relevance to human health and wild Drosophila species for their diversity and ecological realism. In Specific Aim 1, Hawaiian Drosophila species, which have naturally diverse microbiomes, will be used to identify relationships between microbiome structure (diversity and composition) and stability during infection by a bacterial pathogen. Next, causal relationships between microbiome structure and stability will be tested by manipulating the microbiome of D. melanogaster and exposing the flies to the pathogen. Specific Aim 2 will use populations of a single Drosophila species, which have naturally evolved under different temperatures, to test if adaptation to temperature affects how the microbiome and host respond to pathogen infection. In both specific aims, microbiome structure will be measured by DNA sequencing of microbial phylogenetic markers (16S, ITS), which identify the microbial taxa present and their relative abundances. Microbiome function will be assessed using shotgun metagenomics and transcriptomics, which predict functional capacity based on gene orthologues. Pathogen-induced microbiome perturbation will be measured as the change (before and after infection) in microbiome structure and function. Stability is the inverse of perturbation, i.e., the ability to avoid change despite disturbance. Effects of microbiome structure on stability will be determined by testing how microbiome structure prior to infection affects the magnitude of perturbation after infection. This project will generate knowledge on microbiome structure-stability relationships, which will provide a foundation for future research to understand the mechanisms underlying stability and resilience and consequences for host health.

项目总结-病原体感染后微生物组稳定性的决定因素 人类微生物组（即，存在于体内和体表的微生物的集合体）影响人类健康 发展先行者的要求微生物组组成（存在的微生物物种）和多样性（数量） （微生物）会影响微生物的功能。干扰，如抗生素，饮食变化，环境 压力或病原体感染可引起微生物组的变化（扰动），这可影响 微生物组功能和人类健康。干扰对微生物组和人类健康的影响可以 通过微生物组稳定性来缓解，微生物组稳定性是微生物组维持稳定结构（多样性）的能力 和组成）和功能，尽管干扰。了解控制微生物组稳定性的因素 因此对人类健康很重要。传染病和温度胁迫是两种干扰， 由于疾病的反复爆发和人为引起的气候变化，人类健康日益受到关注。的 拟议研究的长期目标是了解气候和疾病如何影响微生物组， 哪些因素控制着微生物组对这些干扰的抵抗力和恢复力。具体目标是：（1） 确定病原体感染期间微生物组多样性和组成如何影响微生物组稳定性;（2） 以确定长期温度变化如何影响微生物组对病原体感染的反应。的 该项目将利用模式生物黑腹果蝇的易处理性和与人类的相关性， 健康和野生果蝇物种的多样性和生态现实主义。具体目标1，夏威夷 果蝇物种具有天然多样的微生物组，将用于确定 微生物组结构（多样性和组成）和细菌病原体感染期间的稳定性。接下来， 将通过操纵微生物组来检验微生物组结构和稳定性之间的因果关系 氏盐并将苍蝇暴露于病原体。具体目标2将使用一个单一的人口 果蝇物种，在不同的温度下自然进化，以测试是否适应 温度影响微生物组和宿主对病原体感染的反应。在这两个具体目标中， 微生物组结构将通过微生物系统发育标记（16 S，ITS）的DNA测序来测量， 其鉴定存在的微生物分类群及其相对丰度。将评估微生物组功能 使用鸟枪宏基因组学和转录组学，根据基因预测功能能力， 直系同源物。病原体诱导的微生物组扰动将被测量为变化（之前和之后）。 微生物组结构和功能。稳定性是扰动的逆，即，能力避免 改变，尽管有干扰。微生物组结构对稳定性的影响将通过测试 感染前的微生物组结构影响感染后的扰动幅度。该项目将 产生关于微生物组结构-稳定性关系的知识，这将为未来的研究奠定基础。 开展研究，以了解稳定性和复原力的基本机制以及对东道国健康的影响。