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: 10242686
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242686
• 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 microbiome; gut microbiota; human subject; immune activation; immune function; inflammatory disease of the intestine; 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.

项目总结