Multi-omics characterization of HIV-associated changes in the gut microbiome and host mucosal immunity

HIV相关肠道微生物组和宿主粘膜免疫变化的多组学表征

• 批准号: 10466926
• 负责人: Douglas Kwon
• 金额: $ 84.69万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10466926
• 关键词: 16S ribosomal RNA sequencing; AIDS/HIV problem; Address; Africa South of the Sahara; African; Bacterial Translocation; Biological Assay; Biology; Boston; CD4 Positive T Lymphocytes; Chronic; Communities; Coupled; Data; Data Analyses; Databases; Diabetes Mellitus; Disease; Disease Progression; Environment; Failure; Feces; Functional disorder; Generations; Genes; Genus staphylococcus; Goals; Gut associated lymphoid tissue; HIV; HIV Infections; Human; Hyperglycemia; Immune; Immune response; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunology; Impairment; In Vitro; Individual; Infection; Inflammatory; Inflammatory Bowel Diseases; Institutes; Intestinal Mucosa; Intestines; Lead; Link; Measures; Mediating; Metabolic; Metagenomics; Microbe; Modeling; Molecular; Mucosal Immunity; Mucous Membrane; Mutation; Obesity; Pathogenesis; Patients; Permeability; Phenotype; Plasma; Population; Process; Publishing; Resolution; Resources; Role; STAT3 gene; Sampling; Science; T-Lymphocyte; Technology; Tissues; Uganda; Universities; Virus Diseases; Work; antiretroviral therapy; bacterial community; base; burden of illness; cohort; commensal microbes; data access; exhaustion; experimental study; geographic difference; gut inflammation; gut microbiome; gut microbiota; human subject; immune activation; immune function; innovation; intestinal epithelium; lentiviral-mediated; metabolomics; metatranscriptomics; microbial; microbial community; microbiome; microbiome alteration; microbiome analysis; microbiome composition; multiple omics; new technology; nonhuman primate; novel; pathobiont; screening; skin microbiome; stem cells

PROJECT SUMMARY The human gut harbors an enormously diverse community of commensal microbes that has co-evolved with humans to assist in critical host metabolic and immune functions. The impact of changes in the microbiome on disease states as diverse as diabetes, obesity, immunodeficiency, and inflammatory bowel disease (IBD) is only now being recognized. Human immunodeficiency virus (HIV) infection has profound effects on the intestinal mucosal environment with a hallmark of infection being a rapid depletion of CD4+ T cells within gut associated lymphoid tissue (GALT) and impairment of intestinal epithelial barrier function. Despite this, our understanding of intestinal microbiota changes occurring with HIV infection and the potential effects of these changes on host immunity and HIV disease progression remains incomplete, particularly in populations in sub-Saharan Africa, where HIV disease burden is greatest. Our prior published work is one of only a few studies to examine HIV- associated changes in the gut microbiome in sub-Saharan Africa. Limitations of published studies of HIV- associated alterations in the gut microbiome include 1) the use of 16S rRNA gene sequencing to identify bacterial taxa abundances but failure to resolve differences at the strain level, 2) lack of deep functional characterization of bacterial communities, 3) characterization of HIV-infected populations in developed regions only, and 4) lack of integration with mechanistic experiments. Our proposal addresses the limitations in the field by 1) using comprehensive culturomic, metagenomic, metatranscriptomics, and metabolomic approaches to fully characterize the gut microbiome at the strain level, 2) assessing its function, 3) integrating studies of a U.S. population along with subjects from sub-Saharan Africa, where HIV burden is greatest and where it is known that baseline gut microbiota differ significantly from those living in developed regions and 4) integrating these analyses with mechanistic studies using in vitro and ex vivo models. Overall, the combination of unique, well- characterized human samples analyzed with cutting-edge assays that combine computational and immunologic approaches is highly innovative and will seek to identify bacterial strains, genes, and molecules that impact HIV disease in the U.S. and sub-Saharan Africa. This work will additionally lead to the generation of a multi-‘omic database that will serve as a resource for the field, including community access to data and bacterial strains isolated from samples analyzed in this project.

项目摘要 人类的肠道与与之共同发展的评论微生物的多样化社区。 人类有助于宿主代谢和免疫功能。 疾病状态与糖尿病，肥胖，免疫缺陷和炎性肠病（IBD）一样多样 现在被识别。 感染的标志是肠道中的CD4+ T细胞快速部署的粘膜环境 淋巴组织（GALT）和肠上皮屏障功能受损。 HIV HIV HIV HIV HIV HIV HIV HIV发生的肠道微生物群的变化对宿主的潜在影响对宿主的潜在影响 免疫和艾滋病毒疾病进展仍然不完整，尤其是在撒哈拉以南非洲的人群中， 艾滋病毒疾病负担最大。 撒哈拉以南非洲肠道微生物组的相关变化。 肠道微生物组的相关改变包括1）使用16S rRNA基因测序鉴定细菌 分类群丰度，但无法在应变水平上解决差异，2）缺乏深度功能表征 细菌群落，3）仅在发达区域中表征HIV被hiv的Poptioneds，4）缺乏 与机械经验的集成。 全面的培养基，宏基因组，元文字组学和代谢组方法完全 在应变水平上表征肠道微生物组，2）评估是功能性的，3）整合美国的研究 人口以及来自非洲以下非洲的受试者，时间最高，众所周知 基线肠道菌群与发达区域的生活显着不同4） 使用体外和离体模型进行机械研究的分析。 用尖端测定法分析的人类样品，结合了计算和免疫学 方法具有很高的创新性，并将寻求鉴定影响影响艾滋病毒的双方菌株，基因和分子 在美国和撒哈拉以外的疾病。 将作为该领域的资源的数据库，使社区访问数据和细菌锯齿 从该项目中分析的样品中分离出来。