Deciphering ExPEC Virulence Mechanisms

描述(申请人提供)：肠外致病性大肠杆菌(ExPEC)可引起多种疾病，包括尿路感染、败血症和新生儿脑膜炎。在美国，这些感染每年影响670万到860万人，代价是15亿到23亿美元。目前对ExPEC引起的感染的治疗方案往往无效或因获得抗生素耐药性而变得无用。除了流行病学研究和遗传筛选外，对几个ExPEC分离株的基因组测序已经确定了许多假定的毒力因素。然而，在大多数情况下，这些细菌因子在感染过程中的功能作用仍然是个谜。最近，我们利用斑马鱼胚胎开发了一种新的感染模型，可以在细菌接种到血液或心包腔后对ExPEC毒力机制进行大规模筛选和功能分析。在这个模型系统中对几个已测序的ExPEC分离物的初步筛选表明，这些微生物的毒力潜力可以以一种生态位依赖的方式显著变化。这些数据表明，ExPEC分离株已经进化出多种可能重叠的策略，以增强特定宿主环境中的生存和生长。在这里，我们建议利用斑马鱼模型系统，结合遗传筛选和基因表达谱，描述在局部和系统感染过程中发挥作用的ExPEC毒力因子和宿主反应途径。拟议研究的最终目标是确定微生物目标，以帮助开发预防和治疗ExPEC引起的感染的改进工具。如果成功，这项工作可能会影响数百万人的生活质量、健康和寿命。新出现的抗生素耐药性在ExPEC分离株中的流行，以及越来越多的高度易感的老年人和免疫功能低下的个人，提供了额外的激励，以促进我们对ExPEC的无数优点和弱点的理解。 公共卫生相关性：肠外致病性大肠杆菌(ExPEC)菌株可导致各种严重疾病，每年影响数百万人，造成数十亿美元的医疗成本和工作时间损失。利用一种新的斑马鱼感染模型，我们建议识别在全身和局部感染期间调节不同ExPEC菌株致病能力的细菌因子和宿主反应。

DESCRIPTION (provided by applicant): Extraintestinal pathogenic Escherichia coli (ExPEC) cause a diverse array of diseases including urinary tract infections, sepsis, and neonatal meningitis. These infections affect 6.7 to 8.6 million individuals each year in the United States, at a cost of $1.5 to $2.3 billion. Current treatment protocols for ExPEC-induced infections are often ineffective or rendered useless by the acquisition of antibiotic resistance. Genomic sequencing of several ExPEC isolates, in addition to epidemiological studies and genetic screens have identified numerous putative virulence factors. However, in most cases the functional roles of these bacterial factors during infection remain enigmatic. Recently, we have developed a novel infection model employing zebrafish embryos that allows for large-scale screening and functional analysis of ExPEC virulence mechanisms following bacterial inoculation into either the blood or pericardial chamber. An initial screen of several sequenced ExPEC isolates in this model system demonstrated that the virulence potential of these microbes can vary significantly in a niche-dependent fashion. These data suggest that ExPEC isolates have evolved multiple, probably overlapping strategies for enhanced survival and growth within specific host environments. Here we propose to utilize the zebrafish model system, in association with genetic screens and gene expression profiling, to delineate ExPEC virulence factors and host response pathways that come into play during both localized and systemic infections. The ultimate goal of the proposed research is to identify microbial targets that will aid the development of improved tools for the prevention and treatment of ExPEC-induced infections. If successful, this work has the potential to impact the quality of life, health, and longevity of millions. The emerging prevalence of antibiotic resistance among ExPEC isolates, as well as growing numbers of highly susceptible elderly and immunocompromised individuals, provide additional incentive for advancing our understanding of the myriad strengths and weaknesses of ExPEC. PUBLIC HEALTH RELEVANCE: Strains of Extraintestinal pathogenic Escherichia coli (ExPEC) cause a diverse array of serious illnesses that affect several million individuals each year, costing billions in health care and time loss at work. Using a novel zebrafish infection model, we propose to identify bacterial factors and host responses that modulate the ability of different ExPEC strains to cause disease during both systemic and localized infections.