A Genomics Based Investigation of the Determinants of Polymicrobial Infectious Disease Outcomes

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 关于整个系统的生物学和这些部分的相互作用的详细问题，而不是 孤立地检查系统的各个部分。此应用程序包含探索动态 病原体、宿主、它们的微生物区系和免疫系统之间的相互作用，目标是提供一种 更全面地了解传染病后果的决定因素。病原体颠覆 宿主细胞通过使用它们的基因产物来操纵细胞存活和复制的途径；反过来，宿主 细胞通过基因表达的变化对入侵的病原体做出反应。破译这些复杂的 时间和空间动态以确定新的毒力因子或寄主反应途径是至关重要的 对传染病过程有全面的了解。然而，即使是这些方法也没有完全采用 考虑到相互作用的复杂性，考虑到正常的微生物区系也是这些 互动。正常微生物区系中的大多数成员以互助者的形式存在，它们相互关联地生活。 不会引起疾病。然而，寄主、其微生物群和病原体之间的相互作用 宿主免疫反应的背景、合并感染、抗微生物疗法或疫苗可以极大地影响 疾病结局。高通量技术与生物问题的结合突出了 基因组学作为一个研究领域的演变，从几年前的一个严格的观察工具，到现在 作为检查疾病过程和整个人类健康的一个组成部分。基因组学 视点正在变得更加完整，因为我们可以开始同时表征宿主的相互作用， 病原体和微生物区系。当前的应用程序采用了一种系统的方法来检查 单一病原体，或病原体所在的生态系统，但检查其他微生物的影响 以及宿主因素对传染病过程的影响。来自这些复杂交互的数据的集成 为更深入地了解健康和疾病提供了基础。这项提案包括一项高度 以加州大学基因组科学研究所为中心的合作研究小组 马里兰大学和纽约大学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。我们期望这些研究将解决有关知识方面的重大差距。 病毒、细菌、真菌和寄生虫的分子发病机制。

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 and the interactions of those parts, rather than examining parts of the system in isolation. This application contains studies that explore the dynamic interactions between pathogens, hosts, their microbiota and the immune system with the goal to provide a more comprehensive understanding of the determinants of infectious disease outcomes. Pathogens 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 changes in gene expression. Deciphering these complex temporal and spatial dynamics to identify novel virulence factors or host response pathways is essential for complete understanding of the infectious disease process. However, even these approaches don't fully take into account the complexity of the interactions, given that the normal microbiota are also key players in these interactions. The majority of the members of the normal microbiota exist as mutualists that live in association with the host without causing disease. Yet, the interactions of a host, its microbiota, and a pathogen in the context of the host immune response, co-infections, anti-microbial therapies, or vaccines can greatly affect disease outcome. 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 current application takes a systematic approach to the examination of not just a single pathogen, or the ecosystem that the pathogen is part of, but examines the impact of the other microbes and host factors on the infectious disease process. 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 and New York University 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.