Virulence regulation in group B Streptococcus

描述（由申请方提供）：尽管在孕产妇产前筛查和围产期抗生素预防方面取得了进展，但B组链球菌（无乳链球菌或GBS）感染仍然是新生儿败血症的主要原因，也是老年人和慢性病成人严重感染的日益重要的原因。虽然GBS有能力在易感宿主中产生危及生命的感染，但它通常表现为无害的寄生虫，定植在30%或更多无症状成人的胃肠道或生殖道。GBS适应其人类和动物宿主，以及从寄生虫向侵入性感染的转变，可能涉及细菌对各种宿主环境中遇到的条件的反应。初步研究已经确定了一个假定的双组分组氨酸激酶反应调节系统在GBS控制至少两个突出的毒力决定因素的表达。在两个独立的菌株背景中，反应调节因子CsrR的失活导致GBS β-溶血素/溶细胞素的显著增加和CAMP因子的同样显著的减少，CAMP因子是一种分泌的蛋白质，其与金黄色葡萄球菌的β-溶细胞素产生协同溶血。该项目的总体目标是表征这种新型双组分调节系统在GBS适应人类宿主中的潜在作用，既作为一种寄生生物又作为一种侵入性病原体。这一目标将通过三个具体目标来实现：（1）建立GBS中CsrR/CsrS这一新的多基因调控系统的转录调控的分子基础;（2）利用DNA微阵列技术研究Csr系统对全局基因调控的影响;和（3）通过研究Csr调节系统对人上皮细胞的粘附和侵袭的作用来表征Csr调节系统在体内发病机制中的作用，对宿主免疫效应物的抗性，以及对GBS感染动物模型中的毒力的影响。在不同的环境条件下的Csr调节的基因表达的体外测定的结果一起从细胞培养和体内感染模型中获得的将特定的环境刺激GBS适应宿主环境的Csr系统的功能。总之，这些研究将拓宽我们对毒力基因调控如何促进GBS发病机制的理解。

DESCRIPTION (provided by applicant): Despite progress in maternal prenatal screening and peripartum antibiotic prophylaxis, group B Streptococcus (Streptococcus agalactiae or GBS) infection remains a leading cause of neonatal sepsis and an increasingly important cause of serious infection in elderly and chronically ill adults. Although GBS has the capacity to produce life-threatening infection in susceptible hosts, it usually behaves as a harmless commensal, colonizing the gastrointestinal or genital tract of 30% or more of asymptomatic adults. Adaptation of GBS to its human and animal hosts, and the transition from commensalism to invasive infection, is likely to involve a repertoire of bacterial responses to conditions encountered in various host environments. Preliminary studies have identified a putative two-component histidine kinase-response regulator system in GBS that controls expression of at least two prominent virulence determinants. Inactivation of the response regulator, CsrR, in two independent strain backgrounds resulted in a striking increase in the GBS beta-hemolysin/cytolysin and an equally striking reduction in CAMP factor, a secreted protein that produces synergistic hemolysis with the beta-lysin of Staphylococcus aureus. The overall objective of this project is to characterize the potential role of this novel two-component regulatory system in adaptation of GBS to the human host, both as a commensal organism and as an invasive pathogen. This goal will be accomplished through three specific aims: (1) to establish the molecular basis of transcriptional regulation by CsrR/CsrS, a novel multigene regulatory system in GBS; (2) to determine, using DNA microarrays, the effects of the Csr system on global gene regulation; and (3) to characterize the role in pathogenesis of the Csr regulatory system in vivo by studying its effects on adhesion and invasion of human epithelial cells, resistance to host immune effectors, and effects on virulence in animal models of GBS infection. Results of in vitro assays of Csr-regulated gene expression under different environmental conditions together those obtained from cell culture and in vivo infection models will link specific environmental stimuli to the functions of the Csr system in GBS adaptation to the host environment. Together, these studies will broaden our understanding of how virulence gene regulation contributes to GBS pathogenesis.