Examination of Enteric Pathogens with Multi-Omic Approaches

用多组学方法检查肠道病原体

基本信息

批准号：
8711692
负责人：
David A Rasko
金额：
$ 128.28万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-15 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8711692
关键词：
Address Animal Model Bacteria Biological Models Cell Culture Techniques Cessation of life Clinical Trials Coculture Techniques Communicable Diseases Data Developed Countries Disease Disease Outbreaks Disease Outcome Enteral Epidemiologic Studies Evolution Gastrointestinal tract structure Gene Expression Profile Genes Genetic Variation Genome Genomics Goals Human Human body Immune Immune response In Vitro Individual Infection Lead Maryland Metagenomics Microbe Modeling Molecular Epidemiology Morbidity - disease rate Organism Organoids Pathogenesis Play Population Process Role Severity of illness Signal Transduction Surveys System Techniques Technology Time Universities Vaccinated Vaccination Vibrio cholerae Virulent Work base enteric pathogen enterotoxigenic Escherichia coli gastrointestinal genome sequencing human subject in vivo in vivo Model insight metagenome microbiome monolayer mortality novel pathogen pressure rRNA Genes research study response transcriptomics trend vaccine development volunteer

项目摘要

Both of the organisms to be studied in this proposal, V. cholerae and ETEC, are significant causes of morbidity and mortality due to diarrheal illness in less economically developed countries leading to hundreds of thousands of deaths each year. Additionally, each has been implicated in outbreaks in recent years that have been addressed with genomic techniques. These outbreaks have highlighted the utility of genome sequencing in the analysis of the dissemination, evolution and pathogenesis of these pathogens. We will take advantage of two ongoing clinical trials at the Center for Vaccine Development on the University of Maryland campus to examine the host:pathogen interactions during a challenge with fully virulent V. cholerae or ETEC. We will be examining this interaction at the level of pathogen signaling and response, human immune response, and interactions with the existing microbiota. Small animal models for enteric diseases are not truly representative of the disease process that occurs in humans, so the ability to directly study the host and pathogen response within human subjects in a controlled manner is a unique opportunity and will provide many novel insights into these interactions. This will be the first time, to our knowledge that an enteric pathogen will be examined for the genetic variation that occurs and/or is selected for during transit through humans. Additionally, by using the most cutting edge 'omic technologies to examine the microbiota, metagenome and metatranscriptome, as well as immunological studies, we will be able to begin to model the interaction during the infectious process. In addition to the studies within the human host, we extend the examination of the transcriptional interactions to the use of an organoid model system. Since we realize that the human challenge experiments are rare, we hope to develop this organoid system as a more representative surrogate model for infection studies. We increase the complexity of the model system by coculturing the pathogens with other pathogens that have been identified to be isolated together in diarrheal studies, as well as we will extend the microbiota studies to co-culture the species/genera identified with an increased severity of disease in the challenge studies. These studies will provide an unprecedented view into the interaction of the host, pathogen and resident microbiota.

本提案中要研究的两种生物体，霍乱弧菌和 ETEC，是导致在经济欠发达国家，腹泻疾病导致数百人发病和死亡每年有数千人死亡。此外，近年来，每一个都与疫情爆发有关已通过基因组技术得到解决。这些爆发凸显了基因组的效用测序分析这些病原体的传播、进化和发病机制。我们将利用大学疫苗开发中心正在进行的两项临床试验马里兰州校园检查宿主：在与全毒力霍乱弧菌的挑战中病原体的相互作用或 ETEC。我们将在病原体信号传导和反应、人类免疫反应以及与现有微生物群的相互作用。肠道疾病小动物模型不能真正代表人类发生的疾病过程，因此直接研究的能力以受控方式在人类受试者体内进行宿主和病原体反应是一个独特的机会，并且将为这些相互作用提供了许多新颖的见解。据我们所知，这将是第一次将检查肠道病原体在运输过程中发生和/或选择的遗传变异通过人类。此外，通过使用最前沿的“组学”技术来检查微生物群，宏基因组和宏转录组，以及免疫学研究，我们将能够开始建模传染过程中的相互作用。除了在人类宿主内的研究之外，我们还扩展了检查转录相互作用与使用类器官模型系统的关系。既然我们意识到人体挑战实验很少见，我们希望将这种类器官系统开发为更多感染研究的代表性替代模型。我们通过共培养增加模型系统的复杂性该病原体与已确定在腹泻中一起分离的其他病原体研究，以及我们将扩展微生物群研究以共培养用挑战研究中疾病的严重程度增加。这些研究将为我们提供前所未有的视角宿主、病原体和常驻微生物群的相互作用。