Deciphering ExPEC Virulence Mechanisms

描述（由申请人提供）：肠外致病性大肠杆菌（ExPEC）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670万至860万人，造成15亿至23亿美元的损失。目前的治疗方案往往是无效的或无效的获得抗生素耐药性。对几种外源性大肠杆菌分离株的基因组测序，加上流行病学研究和基因筛选，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谜。最近，我们开发了一种利用斑马鱼胚胎的新型感染模型，该模型允许在将细菌接种到血液或心包腔后进行大规模筛选和功能分析exic毒力机制。在该模型系统中对几个测序的ExPEC分离株的初步筛选表明，这些微生物的毒力潜力可以以一种依赖于生态位的方式显着变化。这些数据表明，ExPEC分离株已经进化出多种可能重叠的策略，以增强在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，来描绘在局部和全身感染中起作用的exic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靶点，这将有助于开发用于预防和治疗u诱导感染的改进工具。如果成功，这项工作有可能影响数百万人的生活质量、健康和寿命。在ExPEC分离株中出现的抗生素耐药性的流行，以及越来越多的高度易感的老年人和免疫功能低下的个体，为我们进一步了解ExPEC的无数优势和劣势提供了额外的动力。

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.