The Lung DNA Virome in Health and Disease

健康和疾病中的肺 DNA 病毒组

• 批准号: 9926300
• 负责人: Frederic D Bushman
• 金额: $ 74.96万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926300
• 关键词: Acute; Affect; Animals; Archaea; Aspirate substance; Bacteriophages; Blood; Bronchoalveolar Lavage; Cells; 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; Infrastructure; Injury; Knowledge; Lung; Lung Transplantation; Lung diseases; Metagenomics; Methods; Microbe; Molecular Virology; Nature; Organ Donor; Pathologic; Phase; Phenotype; Plasma; Regulation; Respiratory Failure; Respiratory System; Role; Sampling; Sarcoidosis; Science; Shotguns; Single Stranded DNA Virus; Site; Smoking; Specimen; Sputum; T-Lymphocyte; Taxonomy; Testing; Time; Torque; Viral; Virus; Work; bacterial community; bacteriome; cigarette smoking; design; endotracheal; experience; fungus; human disease; human virome; immune reconstitution; innovation; insight; lung injury; lung microbiome; member; microbial community; microbiome research; microbiota; mycobiome; novel; novel virus; particle; personalized approach; 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病毒蛋白 我们与居民微生物群建立了相互依存的关系，这极大地影响了人类健康 和疾病。微生物群落在不同的身体部位不同，并且在每个身体部位都有明显的后果。 人类与微生物之间的关系最广泛地研究了我们的细菌 社区，但对人类病毒瘤的了解少得多，尤其是在呼吸道中。 在初步研究中，我们使用shot弹枪宏基因组学来研究几个受试者的肺病毒蛋白。 我们建立了有效的方法来纯化病毒颗粒和序列的计算方法 组装和分类任务。这揭示了噬菌体和动物细胞病毒的多样性。最突出的 我们发现了扭矩病毒肺（TTV）的高水平，这是一个极端的小型DNA病毒家族 高变差，我们确定了一组新型的小圆形DNA病毒，与任何同源性有限 先前描述的病毒（我们称其为“与人类Circo相关的病毒”； HCRV）。众所周知，TTV在血液中 在有效的宿主免疫控制下，但既不控制TTV的细胞免疫反应 已经研究了肺特异性调节。关于肺特异性HCRV一无所知，因为我们识别 他们第一次来这里。这些发现突出了当前知识中的主要差距：肺及其如何 无处不在的病毒社区相互作用和相互影响，尤其是丰富的小单一 滞留的DNA病毒？吸烟的影响是肺损伤的主要原因的影响？是这些 病毒和宿主对它们的免疫反应，导致肺部损伤和/或驱动肺部感染 疾病？为了加速对肺病毒蛋白的了解以及与肺部健康与疾病的关系，我们将： 阶段1（R61）1-2年：为了为进一步的进步设定阶段，我们将（1）定义TTV的分布 ＆HCRV来自严重肺病受试者的呼吸道样品（“极端表型”）； （2） 生成和询问肺病毒素宏基因组数据集，以共享其他新型呼吸道DNA病毒 在个人中； （3）对T细胞免疫反应的新型“个性化”评估 高变量TTV和HCRV免疫复杂的方法； （4）生成支气管肺泡的存储库 灌洗（BAL）标本，代表了第2阶段的病毒瘤和免疫学分析高优先级的肺部疾病。 第2阶段（R33）年3 - 5年：我们将（1）定义肺病毒蛋白成分与病毒群之间的关系 靶向免疫反应和高优先级的肺部疾病； （2）确定吸烟的影响 肺病毒蛋白和血浆病毒蛋白和靶向病毒蛋白的免疫反应； （3）定义分子病毒学 HCRV，TTV和其他与肺有关的小型DNA病毒。 该项目旨在结合发现/假设生成科学以及具体 RFA HL-17-002中概述的假设测试研究，我们预计这将为您提供新的见解 肺中病毒蛋白的性质以及在肺部健康和疾病中的作用。