Host, Pathogen, and the Microbiome: Determinants of Infectious Disease Outcome

描述(申请人提供)：高通量基因组学和相关技术的出现使人们有能力开始询问关于整个系统生物学的详细问题，而不是孤立地检查系统的某些部分。这项应用包含探索病原体、宿主、其微生物区系、免疫系统和环境之间动态相互作用的研究，目的是更全面地了解传染病结局的决定因素。这些项目的目标是与人类受试者的独特样本相关的高度优先的病毒、细菌、真菌和寄生虫病原体，以及适当情况下每个项目的相关动物疾病模型。病原体经常通过利用它们的基因产物来操纵细胞生存和复制的途径来颠覆宿主细胞；反过来，宿主细胞通过基因表达的级联变化来响应入侵的病原体。破译这些复杂的时间和空间动态，以确定新的毒力因子或宿主反应途径，对于全面了解传染病的过程是至关重要的。高通量技术与生物学问题的结合突显了基因组学作为一个研究领域的演变，从几年前的严格观察工具，到成为检查疾病过程和整个人类健康的不可或缺的部分。基因组学的观点正在变得更加完整，因为我们可以开始同时描述寄主、病原体和微生物区系之间的相互作用。来自这些复杂相互作用的数据的整合正在为更深入地了解健康和疾病提供基础。这项提议包括一个以马里兰大学基因组科学研究所为中心的高度合作的研究小组，他们是各自病原体生物学领域的专家，但也是基因组学领域的先驱。我们预计，这些研究将解决与病毒、细菌、真菌和寄生虫病原体的分子发病机制相关的知识以及宿主对感染的反应方面的主要空白。 相关性：传染病在世界各地造成严重的发病率和死亡率。本申请中描述的工作将使用当前基于基因组学的方法来揭示有关致病因子及其感染的宿主的新信息。科学界将能够利用这些研究的结果来设计更好的诊断、抗微生物化合物和疫苗。 项目1：中大西洋蝙蝠新出现的MERS冠状病毒和冠状病毒的组学研究 项目负责人(PL)：弗里曼，M. 描述(由申请人提供)：新出现的病毒代表着世界各地的重大公共卫生威胁。严重急性呼吸综合征冠状病毒(SARS-CoV)和最近出现的中东呼吸综合征冠状病毒(MERS-CoV)是在世界各地能够并已经导致致命疾病的越来越多的紧急病毒中的两种。至关重要的是，我们必须了解其在动物和人类中增加发病的潜在生物学基础。人们还认识到，最近出现的高致病性病毒起源于蝙蝠。蝙蝠遍布各大洲，总数超过1100种。相互关联的蝙蝠生态系统提供了多样化和无穷无尽的新病毒和利基，其中包含数百种以前从未发现的病毒。为了更好地描述最近出现的MERS冠状病毒，我们将使用大规模的基因组方法来揭示MERS冠状病毒与宿主之间的宿主/病原体相互作用。利用高度专业化的基因组学方法，我们还将在马里兰州捕获的蝙蝠中识别新病毒，重点是新型冠状病毒的特征。与最先进的计算生物学和技术核心一起，项目1的PI将表征和识别新出现的和尚未出现的病毒病原体的致病机制。 相关性：2003年出现的SARS-CoV和最近于2012年从蝙蝠身上出现的MERS-CoV突显了了解这些病毒的发病机制和识别蝙蝠体内其他潜在冠状病毒的必要性。该项目中拟议的研究将 确定这些病毒的致病机制，并产生新的化合物，将导致这些感染的治疗方法。

DESCRIPTION (provided by applicant): The advent of high-throughput genomics and associated technologies have afforded the ability to begin to ask detailed questions about the biology of whole systems, rather than examining parts of the system in isolation. This application contains studies that explore the dynamic interactions between pathogens, hosts, their microbiota, the immune system, and the environment, with the goal to provide a more comprehensive understanding of the determinants of infectious disease outcome. The projects target high priority viral, bacterial, fungal, and parasitic pathogens in relation to unique sets o samples from human subjects, when possible, as well as relevant animal models of disease, as appropriate to each project. Pathogens often subvert host cells by using their gene products to manipulate cellular pathways for survival and replication; in turn, host cells respond to the invading pathogen through cascading changes in gene expression. Deciphering these complex temporal and spatial dynamics to identify novel virulence factors or host response pathways is essential for full understanding of the infectious disease process. The integration of the high-throughput technology with the biological question highlights the evolution of genomics as an area of research from a strictly observational tool of only a few years ago, to being an integral part in the examination of the disease process and human health as a whole. The genomic viewpoint is becoming more complete, as we can begin to simultaneously characterize the interactions of host, pathogen and microbiota. The integration of the data from these complex interactions is providing the foundation for a deeper understanding of health and disease. This proposal includes a highly collaborative group of investigators centered within the Institute for Genome Sciences at the University of Maryland who are experts in their respective areas of pathogen biology, but also are pioneers in the field of genomics. We expect that these studies will address major gaps in knowledge related to the molecular pathogenesis of viral, bacterial, fungal and parasitic pathogens and in host responses to infection. RELEVANCE: Infectious diseases cause significant morbidity and mortality around the world. The work described in this application will use current genomics-based approaches to reveal new information about disease-causing agents and the hosts that they infect. The scientific community will be able to use the results of these studies to design better diagnostics, anti-microbial compounds and vaccines. Project 1: Omics studies on the emerging MERS coronavirus and the coronavirome of mid-Atlantic bats Project Leader (PL): Frieman, M. DESCRIPTION (provided by applicant): Emerging viruses represent a significant public health threat around the world. The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the recently emerged Middle East Respiratory Syndrome Coronavirus (MERS-CoV) represent two of an increasing number of emergent viruses that can and have caused lethal disease around the world. It is critical that we understand the underlying biological basis of thei increased pathogenesis in animals and humans. It has also becoming recognized that most recently emerged highly pathogenic viruses have origins in bats. Bats are found on every continent and number over 1100 species in total. The interconnected bat ecosystem provides a diverse and unending supply of novel viruses and niches that harbor hundreds of viruses never before identified. To better characterize the recently emerged MERS-CoV we will use large-scale genomic approaches to uncover the host/pathogen interactions of MERS-CoV with the host. Using highly specialized genomics approaches we will also identify novel viruses in bats caught in Maryland with a focus on the characterization of novel Coronaviruses. Together with the state-of-the-art computational biology and technology Core, the PI of Project 1 will characterize and identify mechanisms of pathogenesis for emerging and yet to emerge viral pathogens. RELEVANCE: The emergence of SARS-CoV in 2003 and the recent emergence of MERS-CoV in 2012 from bats highlight the need to understand the pathogenesis of these viruses and the identification of other potential Coronaviruses in bats. The proposed research in this project will identify the mechanism of pathogenesis for these viruses and produce novel compounds that will lead to therapeutic treatments for these infections.