Functional genomics and systems-level analysis of septicemic E. coli pathogens

肠外致病性大肠杆菌（Extrenteral Pathogenic Escherichia coli，ExPEC）是引起社区和医院感染性疾病的主要致病菌。该病原体是老年人和免疫抑制人群感染性疾病死亡的主要原因。要引起败血症，细菌必须在血清中存活，血清对大肠杆菌具有高度杀菌作用。令人惊讶的是，大肠杆菌血清抗性的分子基础。大肠杆菌和其他革兰氏阴性菌的研究知之甚少。在此，我们建议使用功能基因组学工具-深度RNA测序，蛋白质组学和生物信息学，以表征ExPEC参与血清应答的基因及其表达。这些基因将通过确定它们在侵袭性菌株中的丰度、它们表达的遗传和环境调节以及它们在脓毒症和发病机制中的作用来进一步研究。这些结果将为ExPEC促进血清存活和败血症的机制提供一个全球性的、系统性的展望。这些数据将进一步加深我们对危及生命的血液感染的理解，并确定新的潜在靶点，这将有助于设计疫苗和病原体特异性抗菌剂。因此，我们希望该项目将有助于开发用于检测和预防这些重要的新出现的感染的替代策略。

Virulent ExPEC (Extraintestinal Pathogenic Escherichia coli) strains have emerged as a majorcause of bacterial septicemia, both in community and hospital -acquired disease. This pathogenis a predominant cause of death from infectious diseases among older and immuno-suppressedpeople, Colisepticemia (colibacillosis) is complicated by the abundance of drug resistance andthe broad variety of E. coli serotypes.To cause sepsis, bacteria have to survive in serum, which is highly bactericidal for E. coli.Surprisingly, the molecular basis of serum resistance in E. coli and other Gram negativebacteria is poorly understood. Here we propose to use functional genomics tools - deep RNAsequencing, proteomics and bioinformatics in order to characterize the ExPEC genes involvedin response to serum and their expression. These genes will be further studied by determiningtheir abundance among invasive strains, the genetic and environmental regulation of theirexpression, and their role in sepsis and pathogenesis. The results will provide a global,systematic outlook on the mechanisms utilized by ExPEC to promote serum survival andsepticemia. These data will further our understanding of life-threatening blood infections andidentify new potential targets which will help to design vaccines and pathogen-specific antibacterialagents. Thus, we expect that this project will be instrumental in the development of alternative strategies for the detection and prevention of these important newly-emerging infections.