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Eukaryotic-type signaling mediates two-component regulation of GBS virulence

真核型信号传导介导 GBS 毒力的双组分调节

基本信息

批准号：
8064334
负责人：
Lakshmi Rajagopal
金额：
$ 39.37万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2013-06-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8064334
关键词：
Adult Affinity Age Antibiotic Resistance Appearance Biochemical Birth Complex Cues Cytotoxin Development Disease Environment Enzymes Evaluation Exhibits Family Foundations Future Gene Expression Gene Expression Regulation Gene Family Genes Genetic Transcription Goals Gram-Positive Cocci Hemolysin Human Incidence Infection Knowledge Link Measures Mediating Microbe Molecular Molecular Genetics Neonatal Organism Pathogenesis Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Prevention Prevention strategy Prophylactic treatment Protein-Serine-Threonine Kinases Proteomics Regulation Repression Research Personnel Role Serine Signal Pathway Signal Transduction Site Streptococcal Infections Streptococcus Group B System Therapeutic Threonine Toxin Virulence Virulence Factors Work antimicrobial base early onset late disease onset mutant neonatal sepsis neonate novel pathogen premature prevent programs promoter resistant strain response sensor stillbirth transcription factor

项目摘要

DESCRIPTION (provided by applicant): Streptococcus agalactiae (Group B streptococci, GBS) are p-hemolytic, gram-positive cocci that cause invasive infections in human neonates and adults. Despite significant advances in prevention and treatment of early onset neonatal disease, rates of GBS-related still births, prematurity, late onset neonatal disease and adult infections are not decreased or prevented. These observations emphasize the importance of alternate strategies for prevention of GBS infections. GBS encounters a wide array of host environments during its disease cycle. Hence, it is essential for the pathogen to rapidly adapt to changing external environments to survive and establish successful infections. Bacterial two component signaling (TCS) systems are critical for pathogens to mediate their adaptive responses to the external/host environment. A TCS composed of a sensor kinase CsrS and a response regulator CsrR regulate expression of GBS cytotoxins i.e. p-hemolysin (P-H/C) and CAMP factor. Our studies have shown that GBS also encodes two eukaryotic-type signaling enzymes comprising a sensor kinase Stk1 and its cognate phosphatase Stp1 that regulate virulence. This proposal seeks to extend our understanding of eukaryotic-type signaling in GBS. Our studies show that the eukaryotic-type kinase Stk1 regulates the expression of GBS cytotoxins (P-H/C and CAMP factor) in a manner that is opposite to the TCS, CsrR/CsrS. Our observation that Stk1 requires CsrR for regulation of cytotoxin expression demonstrates a link between eukaryotic-type and two-component signaling in GBS. The objective of this proposal is to elucidate the interaction between Stk1 and CsrR for adaptive gene expression in GBS. In this proposal, we will also define the role of the cognate signaling components Stp1 and CsrS that regulate Stk1 and CsrR activity, respectively. The three specific aims proposed will 1) define the role of Stp1 on Stk1 regulation of CsrR activity 2) establish the effect of the interaction between Stk1 and CsrR on the ability of CsrS to activate CsrR and 3) determine the functional consequence of Stk1 regulation of CsrR activity. A combination of genetic, molecular, biochemical and proteomic approaches are proposed to elucidate the link between eukaryotic-type and two component signaling mechanisms in GBS. These studies will broaden our understanding on signaling mechanisms employed by GBS to mediate its adaptive responses. This work will provide the foundation for future studies on adaptive gene expression by GBS for survival in various host niches and for evaluation of these signaling components as targets in antimicrobial strategies. Our findings will also have widespread implications on novel mechanisms of signaling that regulate adaptive responses in other pathogenic and non-pathogenic microbes.

描述（由申请人提供）：无乳链球菌（B群链球菌，GBS）是一种p溶血性革兰氏阳性球菌，可引起新生儿和成人的侵袭性感染。尽管在预防和治疗早发新生儿疾病方面取得了重大进展，但与gbs有关的死产、早产、晚发新生儿疾病和成人感染的比率并未减少或预防。这些观察结果强调了预防GBS感染的替代策略的重要性。GBS在其疾病周期中遇到各种各样的宿主环境。因此，病原体必须迅速适应不断变化的外部环境才能生存并建立成功的感染。细菌双组分信号（TCS）系统对病原体介导其对外部/宿主环境的适应性反应至关重要。由传感激酶CsrS和反应调节因子CsrR组成的TCS可调节GBS细胞毒素p-溶血素（P-H/C）和CAMP因子的表达。我们的研究表明，GBS还编码两种真核型信号酶，包括传感器激酶Stk1及其同源磷酸酶Stp1，它们调节毒力。这一建议旨在扩展我们对GBS真核型信号的理解。我们的研究表明真核型激酶Stk1以与TCS、CsrR/CsrS相反的方式调节GBS细胞毒素（P-H/C和CAMP因子）的表达。我们观察到Stk1需要CsrR来调节细胞毒素的表达，这表明真核型和GBS中双组分信号传导之间存在联系。本研究的目的是阐明Stk1和CsrR在GBS中适应性基因表达中的相互作用。在本提案中，我们还将定义分别调节Stk1和CsrR活性的同源信号成分Stp1和CsrS的作用。提出的三个具体目标是：1)确定Stp1在Stk1调控CsrR活性中的作用；2)确定Stk1与CsrR相互作用对CsrS激活CsrR能力的影响；3)确定Stk1调控CsrR活性的功能后果。结合遗传、分子、生化和蛋白质组学的方法来阐明真核型和GBS双组分信号机制之间的联系。这些研究将拓宽我们对GBS调节其适应性反应的信号机制的理解。这项工作将为未来研究GBS在不同宿主生态位中生存的适应性基因表达以及评估这些信号成分作为抗菌策略的靶点提供基础。我们的发现也将对调节其他致病和非致病微生物适应性反应的信号新机制产生广泛的影响。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure and substrate recognition of the Staphylococcus aureus protein tyrosine phosphatase PtpA.

金黄色葡萄球菌蛋白酪氨酸磷酸酶 PtpA 的结构和底物识别。

DOI：
10.1016/j.jmb.2011.08.015
发表时间：
2011
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Vega,Carolina;Chou,Seemay;Engel,Katherine;Harrell,MariaE;Rajagopal,Lakshmi;Grundner,Christoph
通讯作者：
Grundner,Christoph

Understanding the regulation of Group B Streptococcal virulence factors.