The Lung DNA Virome in Health and Disease

健康和疾病中的肺 DNA 病毒组

• 批准号: 9303685
• 负责人: Frederic D Bushman
• 金额: $ 27.27万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303685
• 关键词: Acute; Affect; Animals; Archaea; Aspirate substance; Bacteriophages; Blood; Bronchoalveolar Lavage; Cells; Circoviridae; Circovirus; Circular DNA; Communities; Computing Methodologies; DNA; DNA Viruses; Data; Data Set; Disease; Distant; Environment; Family; HIV Infections; Health; Herpesviridae; Human; Human Microbiome; Human body; Immune; Immune Targeting; Immune response; Immunocompromised Host; Immunosuppression; Individual; Inflammation; Injury; Knowledge; Lung; Lung Transplantation; Lung diseases; Metagenomics; Methods; Microbe; Molecular Virology; Nature; Organ Donor; Pathologic; Phase; Phenotype; Plasma; Regulation; Research Infrastructure; Respiratory Failure; Respiratory System; Respiratory tract structure; Role; Sampling; Sarcoidosis; Science; Shotguns; Single Stranded DNA Virus; Site; Smoking; Specimen; Sputum; T-Lymphocyte; Taxonomy; Testing; Time; Torque; Viral; Virus; Work; cigarette smoking; design; endotracheal; experience; fungus; human disease; human virome; innovation; insight; lung injury; member; microbial community; microbiome; microbiota; novel; novel virus; particle; personalized approach; reconstitution; repository; respiratory; respiratory infection virus; response; virome

Abstract: The Lung DNA Virome in Health and Disease We live in an interdependent relationship with our resident microbiota, which strongly influence human health and disease. Microbial communities differ at different body sites, and have distinctive consequences at each. The relationship between humans and their microbes has been most extensively studied for our bacterial communities but far less is known about the human virome, particularly in the respiratory tract. In preliminary studies, we used shotgun metagenomics to investigate the lung virome in several subject groups. We established efficient methods for purification of viral particles and computational methods for sequence assembly & taxonomic assignment. This revealed a diversity of phage & animal cell viruses. Most prominently, we discovered high levels in lung of Torque Tenoviruses (TTV), a family of small DNA viruses with extreme hypervariability, and we identified a novel group of small circular DNA viruses with limited homology to any previously described viruses (which we term “human circo-related virus”; HCRV). It is known that TTV in blood is under potent host immune control, but neither cellular immune responses that control TTV in general nor lung-specific regulation have been investigated. Nothing is known about lung-specific HCRV since we identify them here for the first time. These findings highlight major gaps in current knowledge: How do the lung and its ubiquitous communities of viruses interact and affect each other, particularly the abundant small single stranded DNA viruses? What is the influence of cigarette smoking, a principal cause of lung injury? Are these viruses and host immune response to them contributing to lung injury and/or inflammation that drive lung diseases? To accelerate understanding of the lung virome and relationship to lung health & disease, we will: Phase 1 (R61) Years 1-2: To set the stage for further advancement, we will (1) Define the distribution of TTV & HCRV in respiratory tract samples from severely ill lung disease subjects (“extreme phenotype”); (2) Generate & interrogate lung virome metagenomic datasets for additional novel respiratory DNA viruses shared among individuals; (3) Develop a novel “personalized” assessment of T cell immune responses to hypervariable TTV, and approach to HCRV immune responses; (4) Generate a repository of bronchoalveolar lavage (BAL) specimens representing lung diseases of high priority for virome & immune analysis in Phase 2. Phase 2 (R33) Years 3-5: We will (1) Define the relationship between lung virome constituents & virome- targeted immune responses, and pulmonary diseases of high priority; (2) Determine the impact of smoking on the lung virome and plasma virome, & virome-targeted immune responses; (3) Define the molecular virology of HCRV, TTV & other small DNA viruses relevant to the lung. This project is designed to be a combination of discovery/hypothesis-generating science as well as specific hypothesis-testing studies as outlined in RFA HL-17-002, which we anticipate will provide novel insight into the nature of the virome within the lungs, and role in lung health and disease.

摘要：健康和疾病中的肺 DNA 病毒组 我们与常驻微生物群处于相互依存的关系，这强烈影响人类健康 和疾病。不同身体部位的微生物群落各不相同，并且对每个部位都有不同的影响。 人类与其微生物之间的关系已被最广泛地研究为我们的细菌 但对人类病毒组的了解却少之又少，特别是在呼吸道中。 在初步研究中，我们使用鸟枪法宏基因组学来研究几个受试者组的肺病毒组。 我们建立了有效的病毒颗粒纯化方法和序列计算方法 组装和分类分配。这揭示了噬菌体和动物细胞病毒的多样性。最突出的是， 我们在肺中发现了高水平的扭矩腱病毒 (TTV)，这是一种小型 DNA 病毒，具有极端的 高度变异性，我们鉴定了一组新的小环状 DNA 病毒，与任何病毒的同源性有限 先前描述的病毒（我们称之为“人类圆环相关病毒”；HCRV）。众所周知，TTV在血液中 受到有效的宿主免疫控制，但控制 TTV 的细胞免疫反应一般也不 已研究了肺特异性调节。自从我们确定​​了肺特异性 HCRV 以来，我们对肺部特异性 HCRV 还一无所知 他们是第一次来这里。这些发现凸显了当前知识的主要差距：肺及其器官如何 无处不在的病毒群落相互作用并相互影响，特别是丰富的小型单一病毒群落 搁浅的DNA病毒？吸烟是肺损伤的主要原因，它有何影响？这些是 病毒和宿主对它们的免疫反应导致肺损伤和/或炎症，从而驱动肺部 疾病？为了加速了解肺部病毒组及其与肺部健康和疾病的关系，我们将： 第 1 阶段 (R61) 第 1-2 年：为了为进一步发展奠定基础，我们将 (1) 定义 TTV 的分配 & 严重肺病受试者呼吸道样本中的 HCRV（“极端表型”）； (2) 生成并询问肺病毒组宏基因组数据集，以获取共享的其他新型呼吸道 DNA 病毒 个人之间； (3) 开发一种新颖的“个性化”T细胞免疫反应评估方法 高变 TTV 和 HCRV 免疫反应方法； (4) 生成支气管肺泡存储库 代表第二阶段病毒组和免疫分析高度优先的肺部疾病的灌洗 (BAL) 标本。 第 2 阶段 (R33) 第 3-5 年：我们将 (1) 定义肺病毒组成分与病毒组之间的关系- 有针对性的免疫反应和高度优先的肺部疾病； (2) 确定吸烟对健康的影响 肺病毒组和血浆病毒组，以及病毒组靶向免疫反应； (3) 分子病毒学的定义 HCRV、TTV 和其他与肺部相关的小 DNA 病毒。 该项目旨在将发现/假设生成科学以及特定的 RFA HL-17-002 中概述的假设检验研究，我们预计它将提供对以下问题的新颖见解： 肺部病毒组的性质以及在肺部健康和疾病中的作用。