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

描述（由申请人提供）：传染病在全球造成了惊人的死亡，需要更有效的监测，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知识及其与宿主和昆虫媒介的相互作用方面的重大空白，我们将建立一个传染病基因组中心（GCID）。我们的团队在开发和应用突破性的实验室和分析方法方面有着广泛的记录，并拥有管理大型复杂项目的经验，为传染病研究界提供资源。我们将使用基因组方法来定义生物之间以及微生物群落之间的变异程度。我们的病毒研究将侧重于NIAID的A类优先病原体拉沙病毒和登革热病毒，以及B类优先病原体西尼罗河病毒，以及对热带发展中国家引起发烧的病毒的监测。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医院感染的新原因，以及昂贵的尿路致病性大肠杆菌。真菌研究将集中在具有重要临床影响的主要病原体，新生C.和白色C.，以及最近引起真菌爆发的菌株，包括C. gatti和Fusarium spp.，我们也将研究引起疟疾的寄生虫P. falciparum和它的蚊子载体A. gambiae。在研究这些特殊的高优先级病原体作为模型系统时，我们将制定并培训社区成员使用广泛实用的新方法。我们将对天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，我们将揭示对病原体和宿主相互作用和暴露于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直接（转录）反应。这些应对措施确定了采取干预措施破坏感染和传播周期的潜在新机会。通过将传染病领域的杰出研究人员与尖端实验室和分析方法以及基因组学领域经验丰富的领导者聚集在一起，我们将产生创建跟踪、诊断、治疗和预防传染病的新工具所需的信息。

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.