MtaR-regulated virulence in Streptococcus agalactiae

无乳链球菌中 MtaR 调节的毒力

• 批准号: 7928613
• 负责人: Daniel W Shelver
• 金额: $ 6.76万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7928613
• 关键词: Acute; Address; Amino Acids; Amniotic Fluid; Antibiotics; Bacteria; Biological Process; Blood; Blood Circulation; Characteristics; Clostridium perfringens; Data; Disease; Disease Progression; Elderly; Environment; Escherichia coli; Fetus; Gene Cluster; Gene Expression; Genes; Growth; Human; Immune system; Immunocompromised Host; Individual; Infection; Iron; Knowledge; Link; Meningitis; Metabolic; Metabolism; Metals; Methionine; Microarray Analysis; Modeling; Mutagenesis; Mutation; Nature; Nutrient; Organism; Outcome; Plasma; Pneumonia; Population; Property; Publishing; Regulation; Regulon; Reporting; Screening procedure; Sepsis; Staging; Staphylococcus aureus; Streptococcal Infections; Streptococcus; Streptococcus Group B; Streptococcus pyogenes; System; Testing; Toxin; Upper arm; Virulence; Virulence Factors; Work; in vivo; insight; meetings; mutant; neonate; novel; pathogen; pathogenic bacteria; rapid growth; transcription factor; uptake

DESCRIPTION (provided by applicant). Streptococcus agalactiae (group B Streptococcus; GBS) is a leading cause of invasive infections such as pneumonia, sepsis, and meningitis in neonates. GBS is also an emerging cause of disease among the immunocompromised and elderly. Regulation of virulence determinants and factors important for survival within the host most likely occurs as GBS transitions through different host environments during the progression of disease. However, the regulatory mechanisms in GBS governing its survival within the host and virulence have not been extensively studied. While some pathogens such as Staphylococcus aureus, Streptococcus pyogenes, and Clostridium perfringens are armed with a wide variety of toxins and other molecules that damage the host, it is not apparent that GBS elaborates a large repertoire of `classical' virulence factors. Despite it paucity of virulence factors, GBS can be highly lethal to individuals with immature or poorly functioning immune systems. GBS grows rapidly within the host during acute stages of infection. We posit that ability to acquire nutrients is extremely important to the virulence of GBS. Unlike other pathogens that can synthesize their own nutrients, GBS is fastidious and must scavenge many amino acids and other metabolites from its host. We have discovered that a novel transcriptional regulator, MtaR, is essential for virulence, growth under low-methionine conditions, and transport of methionine. We have identified a gene cluster (the metQ1 region) that is dependent on MtaR for expression and may encode the methionine transport system. The central hypothesis of this proposal is that MtaR-controlled genes permit growth under low-methionine conditions and are important for GBS virulence. Test of the central hypothesis will be conducted through two Specific Aims. 1) Determine the contribution of the metQ1 region to methionine transport, methionine-dependent growth, and virulence. 2) Globally identify genes under the control of MtaR and genes necessary for methionine-dependent growth. Taken together, results from these aims will determine the contribution of methionine transport to GBS virulence and will identify genes that are under the control of MtaR, whether the control is direct or indirect. In addition to the testing our specific hypothesis, completion of the aims may uncover new links between MtaR, virulence, and metabolism. This proposal seeks to identify properties of a pathogenic bacterium, group B streptococcus, that allow it to cause disease.

描述（由申请人提供）。 无乳链球菌（B 族链球菌；GBS）是新生儿肺炎、败血症和脑膜炎等侵袭性感染的主要原因。 GBS 也是免疫功能低下者和老年人中新出现的疾病病因。当 GBS 在疾病进展过程中通过不同的宿主环境时，毒力决定因素和对宿主内生存重要的因素的调节很可能发生。然而，GBS 控制其在宿主内生存和毒力的调节机制尚未得到广泛研究。虽然金黄色葡萄球菌、化脓性链球菌和产气荚膜梭状芽胞杆菌等一些病原体携带有多种毒素和其他损害宿主的分子，但 GBS 并未明显阐述出大量“经典”毒力因子。尽管缺乏毒力因子，GBS 对于免疫系统不成熟或功能不良的个体来说可能具有高度致命性。 GBS 在感染急性期在宿主体内快速生长。我们认为获取营养的能力对于 GBS 的毒力极其重要。与其他可以合成自身营养物质的病原体不同，GBS 非常挑剔，必须从宿主体内清除许多氨基酸和其他代谢物。我们发现一种新型转录调节因子 MtaR 对于毒力、低蛋氨酸条件下的生长以及蛋氨酸的运输至关重要。我们已经鉴定出一个基因簇（metQ1 区域），其表达依赖于 MtaR，并且可能编码蛋氨酸转运系统。该提议的中心假设是 MtaR 控制的基因允许在低蛋氨酸条件下生长，并且对 GBS 毒力很重要。中心假设的检验将通过两个具体目标进行。 1) 确定 metQ1 区域对蛋氨酸转运、蛋氨酸依赖性生长和毒力的贡献。 2) 全面鉴定MtaR控制下的基因和蛋氨酸依赖性生长所需的基因。总而言之，这些目标的结果将确定蛋氨酸转运对 GBS 毒力的贡献，并将识别受 MtaR 控制的基因，无论控制是直接还是间接。除了测试我们的具体假设之外，目标的完成可能会揭示 MtaR、毒力和新陈代谢之间的新联系。 该提案旨在确定 B 族链球菌这一致病细菌的致病特性。