Computational and Experimental Resources for Virome Analysis in Inflammatory Bowel Disease (CERVAID)

炎症性肠病病毒组分析的计算和实验资源 (CERVAID)

基本信息

批准号：
10246192
负责人：
DAVID WANG
金额：
$ 180.9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-18 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246192
关键词：
Acquired Immunodeficiency Syndrome Address Adult Animal Model Animals Bacteria Bacterial Infections Bacteriophages Bioinformatics Biology Caudovirales Cell Culture System Cell Culture Techniques Chronic Classification Clinical Communities Computer Analysis Computer software DNA Viruses Databases Defect Development Digestive System Disorders Disease Disease model Enteral Family Feces Genome Gnotobiotic Goals Health High-Throughput Nucleotide Sequencing Household Human Immune system Infection Inflammatory Bowel Diseases Longitudinal cohort Machine Learning Metabolic Diseases Metadata Metagenomics Modeling Mus National Institute of Diabetes and Digestive and Kidney Diseases Norovirus Open Reading Frames Parasitic infection Pathogenesis Pathogenicity Pathology Patients Play Population Preparation Resource Development Resources Ribosomal RNA Role System Taxonomy Testing Time Viral Viral Genes Viral Genome Virus Virus Diseases bacterial resistance bacteriome base case control cohort computerized tools contig dark matter early childhood enteric virus infection experimental analysis genome annotation gut microbiome human virome improved metagenome microbial molecular sequence database multidisciplinary novel phenomenological models protein function software development stool sample tool virology virome

项目摘要

SUMMARY While the role of the bacterial microbiome in human health and disease is well established, few studies have evaluated the contribution of the virome. Recently, we demonstrated that alterations in the enteric virome in adulthood are associated with diseases such as inflammatory bowel disease (IBD) and AIDS. In a cross- sectional comparison of IBD cases and household controls, a significant expansion of the Caudovirales, an order of phages, and anelloviruses, a family of eukaryotic DNA viruses, was observed. Advancing understanding of the IBD virome beyond this finding is limited by: (1) A lack of well defined longitudinal human cohorts to enable discovery of temporal associations of the virome with health and disease; (2) The challenge of viral “dark matter”. Dark matter refers to the typically >50% of the sequences present in purified virus preparations cannot be classified due to a lack of statistically significant alignment to known reference sequences. Thus, current virome studies effectively assess < 50% of the virome, thereby compromising our ability to detect important associations between the virome and disease; (3) Inadequate experimental systems to manipulate the virome. Although sequencing has identified many novel eukaryotic viruses, there are only cell culture systems for a limited number of viruses; moreover, there are no small animal infection models for newly described viruses. In addition while a tremendous diversity of phage has been identified, only a tiny fraction have known hosts and an even smaller fraction has been cultured. Thus, there are significant barriers that must be overcome to be able to experimentally test the impact of either eukaryotic viruses or phages in murine IBD models. These barriers to understanding the role of the IBD virome will be addressed as follows: Aim 1 will define the enteric virome and bacterial microbiome in a longitudinal cohort of IBD patients and household controls and identify virome associations with IBD. In Aim 2 novel computational tools to identify and characterize viruses present in enteric viromes will be developed, including approaches to classify dark matter. In Aim 3 novel experimental systems for functional virome analysis, including novel cultures of both eukaryotic viruses and phages as well as animal infection models, will be developed with the end goal of evaluating causal roles for the viruses and phage in existing muring IBD models. Together, these Aims will not only address significant barriers in understanding of IBD, but will provide a wealth of tangible computational and experimental resources to advance the general field of virome studies.

概括虽然细菌微生物组在人类健康和疾病中的作用已得到充分证实，但很少有研究最近评估了病毒组的贡献，我们证明了肠道病毒组的改变。成年期的肠道菌群与炎症性肠病 (IBD) 和艾滋病等疾病存在交叉关联。 IBD 病例和家庭对照的局部比较，Caudovirales 的显着扩展，观察到噬菌体和指环病毒（真核 DNA 病毒家族）的进展。除了这一发现之外，对 IBD 病毒组的理解还受到以下因素的限制：(1) 缺乏明确的纵向人类研究 (2) 挑战病毒“暗物质”的含义暗物质通常指纯化病毒中存在的 >50% 的序列。由于缺乏与已知参考的统计显着性一致性，无法对制剂进行分类因此，当前的病毒组研究有效评估了<50%的病毒组，从而损害了我们的研究。检测病毒组与疾病之间重要关联的能力；（3）实验系统不足；尽管测序已经鉴定出许多新的真核病毒，但只有这些病毒。有限数量的病毒的细胞培养系统；此外，还没有小动物感染模型。此外，虽然已鉴定出多种多样的噬菌体，但只有一小部分。部分具有已知的宿主，甚至更小的部分已经被培养，因此，存在显着的障碍。必须克服这个问题才能通过实验测试真核病毒或噬菌体的影响小鼠 IBD 模型。了解 IBD 病毒组作用的这些障碍将如下解决：目标 1 将定义 IBD 患者纵向队列中的肠道病毒组和细菌微生物组，以及家庭控制并识别病毒组与 IBD 的关联。In Aim 2 新颖的计算工具可识别 IBD。将开发肠道病毒组中存在的病毒的特征，包括对暗病毒进行分类的方法 In Aim 3 用于功能病毒组分析的新颖实验系统，包括两者的新颖培养物。开发真核病毒和噬菌体以及动物感染模型，最终目标是评估病毒和噬菌体在现有 IBD 模型中的因果作用，这些目标将不会共同发挥作用。仅解决理解 IBD 的重大障碍，但将提供丰富的有形计算和实验资源来推进病毒组研究的一般领域。