Role of metal transport in Streptococcus sanguinis virulence and competitiveness

金属转运在血链球菌毒力和竞争力中的作用

• 批准号: 9089888
• 负责人: TODD O. KITTEN
• 金额: $ 37.54万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9089888
• 关键词: Acids; Address; Aerobic; Animal Model; Antibiotic Prophylaxis; Antibiotic Resistance; Bacteremia; Bacteria; Biological; Biological Testing; Blood; Blood Circulation; Cell physiology; Cells; Communicable Diseases; Data; Defect; Dental; Dental Care; Dentistry; Disease; Divalent Cations; Drug Targeting; Ecology; Endocarditis; Environment; Family member; Goals; Growth; Health; Heart; Heart Valves; Human; In Vitro; Infection; Infective endocarditis; Lead; Life; Lipoprotein (a); Measures; Mediating; Metabolic; Metabolism; Metals; Microbe; Modeling; Mutation; Operon; Oral; Oral cavity; Oral health; Oryctolagus cuniculus; Oxidative Stress; Pathway interactions; Patient risk; Persons; Pharmaceutical Preparations; Play; Pneumococcal Pneumonia; Prevention; Process; Proteins; Publishing; Rattus; Reactive Oxygen Species; Regulation; Resistance; Ribonucleotide Reductase; Risk; Role; Streptococcus; Streptococcus Viridans Group; Streptococcus mutans; Superoxide Dismutase; System; Testing; Time; Tooth structure; Veillonella parvula; Virulence; Work; acid stress; base; in vitro Model; in vivo; in vivo Model; insight; metabolomics; mortality; mutant; novel; novel strategies; novel therapeutics; oral pathogen; oral streptococci; oxidation; prevent; prophylactic; targeted treatment; transcriptomics; uptake

 DESCRIPTION (provided by applicant): Infective endocarditis is a serious infection of the heart with mortality rates in excess of 20%. This disease is thought to occur when bacteria or other microbes gain access to the blood, attach to previously damaged heart valves, and multiply. The oral or viridans streptococci are a leading cause of this illness, and among this group, Streptococcus sanguinis is especially important. Prevention of endocarditis relies primarily on antibiotic prophylaxis for at-risk patients prior to dental procedures that are likelyto result in bacteremia. However, it is now recognized that most cases of endocarditis result from daily activities that lead to bacteremia, for which dental antibiotic prophylaxis provides no protection. The identification of virulence determinants could provide new targets for novel prophylactic measures capable of providing continuous protection for persons at risk without selecting for antibiotic resistance in the mouth. Toward this goal, we have performed multiple screens of S. sanguinis mutants for loss of endocarditis virulence in an animal model. These studies have identified a lipoprotein, SsaB, that is uniquely important for endocarditis virulence and is also a promising target for therapy or prevention. SsaB, like other members of the family to which it belongs, functions in Mn (and perhaps Fe) uptake, O2 tolerance, and virulence. There are a number of mechanisms by which Mn could contribute to O2 tolerance and virulence, but it is not clear exactly which mechanisms are employed or are most important in streptococci. We have made a number of recent advances in relation to SsaB's potential functions that are novel not just for S. sanguinis, but for any Streptococcus, including characterization of an Mn-dependent ribonucleotide reductase that is essential for aerobic growth, characterization of the biological relevance of superoxide dismutase activity remaining in an ssaB mutant, identifying physiologically relevant in vitro growth conditions that mimic findings from the rabbit endocarditis model, the observation of metal-dependent processing of the SsaB protein, and the finding of an important role for SsaB in acid tolerance. We propose to expand upon these novel findings by examining SsaB regulation and function. This will provide the first test in any Streptococcus of multiple hypotheses generated by our recent findings that are related to metal transport. Given that we know that the primary defect of an ssaB mutant is metabolic, an important part of our study will be an unprecedented metabolomic analysis of O 2 and acid-stressed cells grown under carefully controlled conditions. This will be followed by testing of selected strains in in vitro and in vivo models of oral colonization and endocarditis virulence to test the biological relevance of our findings. The results of this study promise to be directly applicable to a number of other important pathogens and oral colonizers that are known to require Mn. Moreover, this study promises to identify novel approaches to control oral health and prevent infective endocarditis.

 描述（由适用提供）：感染性心内膜炎是心脏的严重感染，死亡率超过20％。当细菌或其他微生物获得血液，附着在先前受损的心脏瓣膜上并繁殖时，这种疾病被认为会发生。口腔或viridans链球菌是这种疾病的主要原因，在这一组中，Sanguinis链球菌尤为重要。预防心内膜炎主要取决于可能导致细菌的牙科手术之前的高危患者的抗生素预防。但是，现在已经认识到，大多数心内膜炎病例是由导致细菌的日常活动引起的，牙齿抗生素预防没有任何保护。病毒确定的识别可以为能够为处于风险的人提供持续保护的新型预防措施提供新的目标，而无需选择口腔中的抗生素耐药性。为了实现这一目标，我们已经在动物模型中进行了多个S. sanguinis突变体的多个筛查，以损失心内膜炎病毒。这些研究已经确定了一种脂蛋白SSAB，该脂蛋白对于心内膜炎病毒至关重要，也是治疗或预防的有希望的靶标。 SSAB与其所属的其他家庭成员一样，在MN（也许是Fe）的吸收，O2耐受性和病毒中起作用。 MN可以通过多种机制有助于O2耐受性和病毒，但是目前尚不清楚哪些机制在链球菌中采用了哪些机制或最重要的机制。 We have made a number of recent advances in relation to SsaB's potential functions that are novel not just for S. sanguinis, but for any Streptococcus, including characterization of an Mn-dependent ribonucleotide reduction that is essential for aerobic growth, characterization of the biologic relevance of superoxide dismutase activity remaining in an ssaB mutant, identifying physically relevant in vitro growth conditions that mimic findings from the rabbit心内膜炎模型，SSAB蛋白的金属依赖性加工的观察以及SSAB在酸耐受性中的重要作用。我们建议通过检查SSAB调节和功能来扩展这些新发现。这将在我们最近与金属转运相关的发现产生的多种假设中提供第一个测试。鉴于我们知道SSAB突变体的主要缺陷是代谢的，因此我们研究的重要部分是对O 2和在仔细控制条件下生长的O 2和酸性压力细胞的前所未有的代谢组分分析。之后，将测试在体外和体内口服定殖和心内膜炎病毒中所选菌株的测试，以测试我们发现的生物学相关性。这项研究的结果承诺是 直接适用于已知需要MN的许多其他重要病原体和口服菌落。此外，这项研究有望确定控制口腔健康并预防感染性心内膜炎的新方法。