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

项目总结 人类肠道中有一个极其多样化的共生微生物群落，它们与 帮助人类发挥关键的宿主代谢和免疫功能。微生物群的变化对 疾病状态多种多样，如糖尿病、肥胖、免疫缺陷和炎症性肠病(IBD) 现在被认出了。人类免疫缺陷病毒(HIV)感染对肠道有深远的影响 感染的标志是肠道内的CD4+T细胞迅速耗尽的粘膜环境 淋巴组织(GALT)和肠上皮屏障功能受损。尽管如此，我们的理解是 HIV感染时肠道微生物区系的变化以及这些变化对宿主的潜在影响 免疫和艾滋病毒疾病的进展仍然不完整，特别是在撒哈拉以南非洲的人口中， 艾滋病负担最重的地方。我们之前发表的研究是为数不多的几项检查艾滋病毒的研究之一。 撒哈拉以南非洲地区肠道微生物群的相关变化。已发表的艾滋病毒研究的局限性- 肠道微生物组的相关变化包括1)使用16S rRNA基因测序来识别细菌 类群丰富，但未能解决菌株水平上的差异，2)缺乏深入的功能表征 细菌群落，3)仅在发达地区描述艾滋病毒感染人群的特征，以及4)缺乏 与机械实验相结合。我们的建议通过以下方式解决该领域的局限性：1)使用 全面的文化、元基因组、元翻译和代谢组学方法，以充分 在菌株水平上表征肠道微生物组，2)评估其功能，3)整合美国的研究。 人口和来自撒哈拉以南非洲的受试者，那里的艾滋病毒负担最重，也是已知的 该基线肠道微生物区系与发达地区的肠道微生物区系显著不同，4)整合这些微生物区系 使用体外和体外模型进行机制研究的分析。总体而言，独特、完美的结合- 用结合了计算和免疫学的尖端分析方法对人体样本进行了表征 方法是高度创新的，将寻求识别影响艾滋病毒的细菌菌株、基因和分子 美国和撒哈拉以南非洲的疾病。这项工作还将导致一种多面体的产生 将作为实地资源的数据库，包括社区获取数据和细菌菌株 从本项目分析的样品中分离出来。

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.