Integrated Genomics of Mucosal Infections

项目总体概要 此申请请求为德克萨斯州医学中心传染病基因组学中心 (GCID) 提供资金 中心 (TMC)，由贝勒的基础科学家和医师科学家组成的多学科综合团队组成 医学院、德克萨斯大学休斯顿公共卫生学院和 MD 安德森癌症中心。 我们 GCID 的总体目标是： i) 利用我们数十年的基因组测序经验 技术与我们著名的临床专业知识，以及使用新颖的离体器官模型 人类肠道和肺功能，创建基于大规模基因组学的平台 询问人体组织中宿主-粘膜病原体相互作用，以及 ii) 利用这一点 基于宿主和微生物发现新的治疗和诊断靶点的平台 基因组和转录组谱。项目 1（PL：A. Maresso 博士）将剖析基因组元素， 赋予肠杆菌科和肠球菌科致病成员与 人类肠粘膜同时也决定了宿主对这种关联的反应。项目 2（PL：M. Estes， 博士）将利用人类诺如病毒和呼吸道合胞病毒全长基因组的综合分析 临床相关患者亚组样本的序列和生态位特征 对病毒复制、重组和进化、疾病诱导和宿主因素的新认识 对感染和发病机制的易感性所必需的。项目 3（PL：D. Corry，医学博士）将检验以下假设： 真菌多样性、毒力和个体对真菌负担的先天免疫反应是持久的、 治疗难治性中度至重度哮喘的新模式，即呼吸道内的真菌负担 呼吸道真菌病（“气道真菌病”）可能在过敏性肺部炎症的发生和持续中起致病作用。 项目 4（PL：P. Okhuysen，医学博士）将建立在项目负责人发现的新型隐孢子虫的基础上 并检验肠道中一种或多种产生吲哚的共生微生物可以预防或 消除隐孢子虫感染。所有四个研究项目都将利用人类肠道和肺类器官 培养物以及由类器官和微型生物反应器提供的特定生态位、明确的微生物群落 阵列培养核心和大量独特的临床样本和分离株，融合了尖端、 由测序技术 (ST) 核心提供的高通量测序策略和技术。 范式转变的发现、数据、工具和试剂将传播给传染病界 由数据管理分析和资源传播 (DMARD) 核心通过最先进的门户提供 由 DNAnexus 开发。结果将是对人类宿主和微生物进行全面的基因分析 感染模型将揭示病原体遗传变异和个体宿主反应表型以提供信息 基于精准医学的治疗和诊断，既针对本提案中的病原体，又针对广泛的病原体 严重影响人类健康的一系列粘膜传染病。

Overall Project Summary This application requests funding for a Genomics Center for Infectious Disease (GCID) in the Texas Medical Center (TMC) that comprises a multidisciplinary, integrated team of basic and physician scientists at Baylor College of Medicine, the University of Texas-Houston School of Public Health, and MD Anderson Cancer Center. The overall goal of our GCID is to: i) leverage our decades of experience in genomic sequencing technology with our renowned clinical expertise, and the use of novel ex vivo organotypic models of human intestinal and pulmonary function, to create a platform for large scale genomics-based interrogation of host-mucosal pathogen interactions in the context of human tissues, and ii) utilize this platform for the discovery of novel therapeutic and diagnostic targets based on host and microbial genomic and transcriptomic profiles. Project 1 (PL: A. Maresso, PhD) will dissect the genomic elements that confer the ability of pathogenic members of the Enterobacteriaceae and Enterococcaceae to associate with the human intestinal mucosa while also determining the host response to this association. Project 2 (PL: M. Estes, PhD) will leverage integrated analyses of human norovirus and respiratory syncytial virus full-length genomic sequences and characterization of the ecological niche of samples from clinically relevant patient sub-groups for new understanding of viral replication, recombination and evolution, induction of disease and host factors required for susceptibility to infection and pathogenesis. Project 3 (PL: D. Corry, MD) will test the hypothesis that fungal diversity, virulence, and individual innate immune responses to fungal burdens underlie persistent, treatment-resistant moderate to severe asthma in a new paradigm whereby fungal burden within the respiratory tract (“airway mycosis”) may have a causative role in development and persistence of allergic lung inflammation. Project 4 (PL: P. Okhuysen, MD) will build on a novel Cryptosporidium discovery made by the project leaders and test the hypothesis that one or more indole-producing commensal microbes in the gut can prevent or eliminate Cryptosporidium infection. All four research projects will utilize human intestinal and lung organoid cultures along with niche-specific, defined microbial communities supplied by the Organoid and Minibioreactor Array Cultivation Core and a large collection of unique clinical samples and isolates, incorporating cutting edge, high-throughput sequencing strategies and technologies supplied by the Sequencing Technology (ST) Core. Paradigm-shifting discoveries, data, tools, and reagents will be disseminated to the infectious disease community by the Data Management Analysis and Resource Dissemination (DMARD) Core through a state of the art portal developed by DNAnexus. The result will be a comprehensive genetic profiling of hosts and microbes in human infection models that will reveal pathogen genetic variants, and individual host response phenotypes to inform precision medicine-based therapeutics and diagnostics, both for the pathogens in this proposal and a broad spectrum of mucosal infectious diseases that severely impact human health.