Virulence regulation in group B Streptococcus

描述(申请人提供)：尽管在孕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，定植于30%或更多无症状成年人的胃肠道或生殖道。GBS对人类和动物宿主的适应，以及从共生到侵入性感染的转变，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GBS中可能存在一个双组分组氨酸激酶-反应调节系统，该系统控制着至少两个重要毒力决定因素的表达。在两个独立的菌株背景下，反应调节因子CsrR的失活导致GBSβ溶血素/细胞溶血素显著增加，而cAMP因子同样显著降低，cAMP因子是一种分泌蛋白，可与金黄色葡萄球菌的β溶血素产生协同溶血作用。这个项目的总体目标是表征这种新的双组分调控系统在GBS适应人类宿主方面的潜在作用，既作为共生有机体，也作为侵袭性病原体。这一目标将通过三个具体目标来实现：(1)建立GBS中新的多基因调控系统CsrR/CSRS转录调控的分子基础；(2)利用DNA微阵列确定CSR系统在全球基因调控中的作用；以及(3)通过在GBS感染的动物模型中研究CSR调控系统对人上皮细胞黏附和侵袭的影响、对宿主免疫效应物的抵抗力以及对毒力的影响，来表征CSR调控系统在体内发病中的作用。不同环境条件下CSR调控基因表达的体外检测结果，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，这些研究将拓宽我们对毒力基因调控在GBS发病机制中的作用的理解。

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.