Infectious Disease Genomics: Pathogen Evolution, Emergence, and Host Interaction

描述(申请人提供的)：传染病在全球造成的惊人损失要求更有效的监测以及新的预防和治疗措施。为了解决我们在关键病原体的基本生物学以及它们与宿主和昆虫媒介之间的相互作用方面的知识差距，我们将创建一个传染病基因组中心(GCID)。我们的团队结合了开发和应用突破性实验室和分析方法的广泛记录，以及管理大型和复杂项目的经验，为传染病研究社区提供资源。我们将使用基因组学方法来定义生物体之间以及微生物群落之间的差异程度。我们的病毒研究将集中在NIAID A类优先病原体拉萨和登革热病毒，以及B类优先病原体西尼罗河病毒，以及热带发展中国家的致热病毒监测。细菌研究将集中在C类优先病原体结核分枝杆菌和碳青霉烯耐药肠杆菌科，这是一种与高死亡率相关的院内感染的新原因，以及代价高昂的致尿性大肠杆菌。真菌研究将集中在具有重大临床影响的主要病原体，新生葡萄球菌和白色念珠菌，以及导致最近真菌暴发的菌株，包括盖蒂葡萄球菌和镰刀菌。我们还将研究导致疟疾的恶性疟原虫及其蚊媒冈比亚按蚊。在研究这些特殊的高优先级病原体作为模型系统时，我们将产生并培训社区成员使用广泛实用的新方法。我们将对自然分离株和实验室衍生的突变体进行测序，并将序列差异与表型联系起来，以帮助解释这种变异在毒力、传播和药物敏感性方面的功能后果。从种群到整个生物体，从动物模型到单细胞，我们将在多个水平上工作，揭示病原体与宿主相互作用和接触药物或杀虫剂的长期(进化)反应，以及宿主和病原体对感染的即时(转录)反应。这些应对措施为干预工作确定了潜在的新机会，以扰乱感染和传播的循环。通过将具有尖端实验室和分析方法的优秀传染病研究人员和经验丰富的基因组学领导者聚集在一起，我们将产生所需的信息，以创建跟踪、诊断、治疗和预防传染病的新工具。 相关性：传染病继续给我们的全球人口造成惊人的社会和经济损失。我们将建立一个中心，利用强大的尖端技术来探索各种危险病原体的生物学及其与宿主的相互作用。这些信息将直接为监测、预防和治疗传染病的新方法提供信息。

DESCRIPTION (as provided by applicant): The staggering global toll taken by infectious diseases calls for vastly more effective monitoring, as well as new preventative and therapeutic measures. To address critical gaps in our knowledge about the basic biology of key pathogens and their interactions with their hosts and insect vectors, we will create a Genomic Center for Infectious Diseases (GCID). Our team combines an extensive track record of developing and applying groundbreaking laboratory and analytical methods with experience managing large and complex projects to produce resources for the infectious disease research community. We will use genomic methods to define the extent of variation among organisms, as well as among microbial communities. Our viral research will focus on the NIAID Category A priority pathogens Lassa and Dengue viruses, and the Category B priority pathogen West Nile virus, as well on surveillance for fever-causing viruses in tropical developing countries. Bacterial studies will focus on the Category C priority pathogens M. tuberculosis and Carbapenem-resistant Enterobacteriaceae, an emerging cause of nocosomial infections associated with high mortality, as well as the costly Uropathogenic E. coli. Fungal research will focus on major pathogens with significant clinical impact, C. neoformans and C. albicans, as well as strains causing recent fungal outbreaks, including C. gattii and Fusarium spp. We will also study both the malaria-causing parasite P. falciparum and its mosquito vector, A. gambiae. In studying these particular high-priority pathogens as model systems, we will produce, and train community members to use, new methods of wide utility. We will sequence natural isolates as well as laboratory-derived mutants, and associate sequence differences with phenotypes to help interpret the functional consequences of this variation with respect to virulence, transmission and drug sensitivity. Working at several levels, from populations to whole organisms, and animal models to single cells, we will reveal the long term (evolutionary) responses to pathogen and host interactions and exposure to drugs or insecticides as well as the immediate (transcriptional) responses of host and pathogens to infection. These responses define potential new opportunities for interventions to disrupt the cycle of infection and transmission. In bringing together outstanding investigators in infectious disease with cutting edge laboratory and analytical methods and experienced leaders in genomics, we will generate the information needed to create new tools to track, diagnose, treat and prevent infectious diseases. RELEVANCE: Infectious diseases continue to take a staggering social and economic toll on our global population. We will establish a center that will employ powerful, cutting edge technologies to probe the biology of a variety of dangerous pathogens and their interactions with their hosts. The information will directly inform new methods to monitor, prevent and treat infectious diseases.