A Multi-Omics Approach to the Examination of Bacterial Co-pathogens

检查细菌共病原体的多组学方法

基本信息

批准号：
10132959
负责人：
David A Rasko
金额：
$ 69.47万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10132959
关键词：
Address Aeromonas Animal Model Automobile Driving Bacteremia Bacteria Bacterial Attachment Site Biological Assay Biological Models Cell Differentiation process Cell model Cell surface Cells Child Clinical Coculture Techniques Communicable Diseases Communities Culture-independent methods Diarrhea Disease Disease Outcome Enteral Epithelial Epithelial Cells Escherichia coli Etiology Eukaryota Feces Future Gene Expression Profile Genes Genetic Transcription Genomics Genotype Human Immune Immune response In Vitro Individual Infection Intestines Investigation Knowledge Laboratories Link Lung Lung infections Metagenomics Modeling Morbidity - disease rate Multicenter Studies Organism Pathogenesis Pathogenicity Pathway interactions Pattern Pneumococcal Infections Property Regulation Respiratory Tract Infections Role Sampling Shigella Side Site Streptococcus pneumoniae Structure Study models Viral Virulence Virus Virus Diseases Wound Infection base chronic wound co-infection comparative genomics diarrheal disease experimental study gut microbiota host microbiome host microbiota human disease in vivo influenza infection influenzavirus insight member metatranscriptomics microbial community microbiome microbiota mortality mouse model multiple omics novel novel therapeutic intervention pathogen pathogenic bacteria pathogenic microbe pathogenic virus prospective respiratory response screening tissue culture transcriptome sequencing transcriptomics

项目摘要

Polymicrobial infections have been linked to important human diseases including chronic wound infections, lung infections, and bacteremia, and can involve different species of bacteria, or bacteria and viruses, or bacteria and eukaryotes. Although the existence of co-pathogens in certain types of disease is established, the complexity of studying co-pathogen interactions using models of pathogenesis has limited our understanding of the role of the different pathogens in these diseases. The scientific premise of the proposed studies is that although polymicrobial infections are linked to infectious diseases, prior experimental studies have focused on single pathogens and have typically not considered the host:pathogen interactions in the presence of co- pathogens or with other members of the host's microbiota. Thus, we will consider not only the impact of co- pathogens on diarrheal illness and lung infections, but will also expand traditional laboratory assays, as well as tissue culture and mouse models to more closely recapitulate the complexity of host:pathogen interactions. We will investigate Aeromonas, E. coli, and/or Shigella in diarrheal co-infections, and the contributions of influenza virus and Streptococcus pneumoniae to respiratory co-infections. In Aim 1 we will use comparative genomics and metagenomics to provide insight into whether there are genes/genotypes, or microbial communities associated with diarrhea and/or co-pathogen interactions of these diarrheal pathogens. In Aim 2 we will further investigate the significance of diarrheal co-pathogens using dual transcriptomics on both the host and bacterial sides to study the impact of co-pathogen interactions in human intestinal enteroids and a mouse model with a simplified intestinal microbiota. In Aim 3, we will diversify our studies of co-infections by characterizing the impact of influenza virus on S. pneumoniae infection of the respiratory tract by performing dual transcriptional analyses with an ex vivo human lung epithelial cell model and an in vivo mouse model of lung infection. Our central hypothesis is that the interaction of multiple pathogens, bacterial-bacterial or bacterial-viral, can result in altered patterns of virulence of each of the pathogens, which will in turn influence interactions with the host, and have a significant role in the disease outcome. We further hypothesize that host responses differ between mono-infections and co-infections. We anticipate that upon completion of the studies we will have identified: (i) differences in the transcriptional profiles of the pathogens and the host in co-infection compared with mono- infection, (ii) genes that were not previously known to be involved in pathogenesis for these important pathogens, and (iii) novel host pathways driving immune and other responses to co-infections. Overall, the findings of this study will advance knowledge of the role of bacterial-bacterial and bacterial-viral co-pathogens in lung infections and diarrheal illness, and will enable future studies of the role of specific eukaryotic and prokaryotic genes and pathways in co-pathogen and/or host:pathogen interactions involved in these diseases. These studies will identify targets for future investigation as novel therapeutic interventions.

多数菌感染已与重要的人类疾病有关，包括慢性伤口感染，肺部感染和菌血症，可能涉及不同种类的细菌，细菌和病毒，或细菌和真核生物。尽管建立了某些类型疾病中的司座原子的存在，但使用发病机理模型研究共生相互作用的复杂性限制了我们对不同病原体在这些疾病中的作用。拟议研究的科学前提是尽管多数菌感染与感染性疾病有关，但先前的实验研究集中在单一病原体，通常不考虑宿主：在共同存在的情况下病原体相互作用病原体或宿主微生物群的其他成员。因此，我们不仅要考虑共同的影响病原体腹泻病和肺部感染，但也将扩大传统实验室测定法，以及组织培养和小鼠模型更紧密地概括了宿主的复杂性：病原体相互作用。我们将研究腹泻共感染中的Aeromonas，大肠杆菌和/或志贺氏菌，以及流感的贡献病毒和肺炎链球菌对呼吸联合感染。在AIM 1中，我们将使用比较基因组学宏基因组学提供有关是否有基因/基因型或微生物群落的洞察力与这些腹泻病原体的腹泻和/或共生相互作用有关。在目标2中，我们将进一步使用双重转录组学对宿主和细菌的双重转录组学研究腹泻司法共生的重要性研究人类肠内肠托动物和与A 简化的肠道菌群。在AIM 3中，我们将通过表征该共同感染的研究多样化流感病毒对呼吸道肺炎链球菌感染的影响通过双重转录用离体人肺上皮细胞模型和肺部感染的体内小鼠模型进行分析。我们的中心假设是多种病原体（细菌 - 细菌或细菌病毒）的相互作用可能导致在每种病原体的毒力模式的改变中，这将影响与宿主的相互作用，并在疾病结局中发挥重要作用。我们进一步假设宿主的反应不同单感染和共同感染。我们预计将在完成研究后，我们将确定：（i）与单一相比感染，（ii）以前不知道这些重要的基因病原体和（iii）新型宿主途径驱动免疫和对共感染的其他反应。总体而言，这项研究的结果将进一步了解细菌 - 细菌和细菌 - 病毒司托的作用在肺部感染和腹泻疾病中，将来可以研究特定真核和副病原和/或宿主中的原核基因和途径：这些疾病中涉及的病原体相互作用。这些研究将确定未来研究的目标是新的治疗干预措施。