Virulence regulation in group B Streptococcus

描述（由申请人提供）：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族链球菌（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年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共生菌，在30%或更多无症状成年人的胃肠道或生殖道中定居。GBS对人类和动物宿主的适应，以及从共生向侵袭性感染的转变，可能涉及对不同宿主环境中遇到的条件的一系列细菌反应。初步研究已经确定了GBS中一个假定的双组分组氨酸激酶反应调节系统，该系统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失活导致GBS β -溶血素/细胞溶血素显著增加，CAMP因子（一种与金黄色葡萄球菌β -溶血素产生协同溶血作用的分泌蛋白）同样显著减少。该项目的总体目标是表征这种新型双组分调控系统在GBS作为共生生物和侵入性病原体适应人类宿主中的潜在作用。这一目标将通过三个具体目标来实现：(1)建立新的GBS多基因调控系统CsrR/CsrS转录调控的分子基础；(2)利用DNA微阵列确定Csr系统对全球基因调控的影响；(3)通过研究Csr调控系统在GBS感染动物模型中对人上皮细胞的粘附和侵袭、对宿主免疫效应物的抗性以及对毒力的影响，表征Csr调控系统在体内的发病机制。不同环境条件下体外测定Csr调控基因表达的结果，以及细胞培养和体内感染模型的结果，将把特定的环境刺激与Csr系统在GBS适应宿主环境中的功能联系起来。总之，这些研究将扩大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.