Integrating microbial glycan arrays with genomic sequences to study host microbe interactions

将微生物聚糖阵列与基因组序列整合以研究宿主微生物相互作用

• 批准号: 10190870
• 负责人: RICHARD D CUMMINGS
• 金额: $ 51万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-03 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190870
• 关键词: Address; Binding; Biological; Carbohydrates; Communities; Complex; Coupled; Data; Databases; Disease; Event; Genomic Library; Genomic approach; Genomics; Goals; Human; Immune; Immune Targeting; Immunity; Immunologic Factor Interaction; Immunologic Factors; Link; Methods; Microbe; Natural Immunity; Nature; Patients; Polysaccharides; Process; Research Personnel; Shapes; Specificity; Structure; Technology; Translating; adaptive immunity; base; design; host microbiota; host-microbe interactions; immune function; microbial; microbial community; microbiota; microorganism antigen; molecular sequence database; normal microbiota; pathogen; pathogenic microbe; response; sequencing platform; success; tool

Summary: While successful immunity relies on the ability of host immune factors to rapidly recognize and respond to a variety of microbial determinants, microbial glycans often serve as the first and most important contact point with host immune factors. However, the binding specificity of most innate and adaptive immune factors toward microbial glycans remains largely unknown. Furthermore, despite the near universal use of genomic sequencing approaches to characterize microbiota, these methods largely fail to identify microbes based upon their unique glycan signatures, precluding the identification of distinct microbial strains with relevant glycan structures when using this approach. In order to effectively overcome current limitations in the study of host-microbial interactions, a platform must be developed that can be used by a wide variety of investigators to define how hosts interact with microbial glycans. Our long-term goal is to develop an integrated platform of microbial glycans and genomic sequences that can be used to define the network of innate and adaptive immune interactions with microbial glycans by a wide range of investigators. Our hypothesis is that microbial glycan arrays populated with pathogens and host microbiota coupled with corresponding genomic sequences will provide a unique and broadly useful strategy to define the specificity of host immune factors toward microbial glycans. Our hypothesis is formulated on the basis of our recent discoveries that innate and adaptive immune factors can interact with a variety of distinct microbial glycans using a platform populated with intact microbes and their corresponding microbial glycans printed in a microarray format. As microbial communities are extremely diverse, our preliminary data also demonstrate that microbes can be specifically isolated from a complex microbial mixture and that microbes and their respective glycans can be similarly printed and interrogated for host immune factor interactions. Furthermore, the genomic library generated from these isolated microbes can be successfully incorporated into traditional approaches designed to study host-microbial interactions, directly democratizing the field. In order to provide the breadth of microbial coverage needed to effectively assess host microbial interactions, we will build on these initial findings to develop an integrated set of tools that will be broadly available to the scientific community through the following specific aims: Specific Aim 1: Develop integrated microbial glycan arrays and genomic databases populated with known pathogens. Specific Aim 2: Develop integrated microbial glycan arrays and genomic databases populated with normal microbial flora highlighted by interactions with host immune factors. Given the fundamental nature of host interactions with microbial glycans and the documented success of array platforms in “democratizing” the field of glycosciences, the integrated tools developed in this proposal will provide a wide range of investigators the opportunity to study host-microbial interactions with significant implications on fundamental and disease-related processes.

摘要：虽然成功的免疫依赖于宿主免疫因子快速识别和 对多种微生物决定因素作出反应，微生物聚糖往往是首要也是最重要的 然而，大多数先天性和适应性免疫的结合点是与宿主免疫因子结合的。 此外，尽管微生物聚糖几乎得到普遍使用，但影响微生物聚糖的因素仍然很大程度上未知。 基因组测序方法来表征微生物群，这些方法很大程度上无法识别微生物 基于其独特的聚糖特征，排除了具有相关特征的不同微生物菌株的鉴定 使用这种方法时可以有效克服目前聚糖结构研究的局限性。 宿主-微生物相互作用，必须开发一个可供各种研究人员使用的平台 定义宿主如何与微生物聚糖相互作用我们的长期目标是开发一个集成平台。 可用于定义先天性和适应性免疫网络的微生物聚糖和基因组序列 我们的假设是微生物聚糖与微生物聚糖的相互作用。 填充有病原体和宿主微生物群以及相应基因组序列的阵列将 提供独特且广泛有用的策略来定义宿主免疫因子对微生物的特异性 我们的假设是基于我们最近的发现，即先天性和适应性免疫。 使用充满完整微生物的平台，因子可以与各种不同的微生物聚糖相互作用 及其相应的微生物聚糖以微阵列格式打印。 极其多样化，我们的初步数据还表明，微生物可以从 复杂的微生物混合物，并且微生物及其各自的聚糖可以类似地打印和 此外，还研究了从这些分离物中产生的基因组文库的宿主免疫因子相互作用。 微生物可以成功地融入到研究宿主微生物的传统方法中 相互作用，直接使该领域民主化，以提供所需的微生物覆盖范围。 有效评估宿主微生物相互作用，我们将在这些初步发现的基础上开发一套综合的 将通过以下具体目标向科学界广泛提供工具： 目标 1：开发集成的微生物聚糖阵列和填充已知病原体的基因组数据库。 具体目标 2：开发集成的微生物聚糖阵列和填充正常微生物的基因组数据库 鉴于宿主的基本性质，微生物菌群通过与宿主免疫因子的相互作用而突出。 与微生物聚糖的相互作用以及阵列平台在该​​领域“民主化”方面的成功记录 糖科学方面，本提案中开发的综合工具将为广泛的研究人员提供 研究宿主-微生物相互作用的机会，对基础和疾病相关具有重大影响 流程。