Internalization of S. mutans in vascular endothelial cells

血管内皮细胞中变形链球菌的内化

• 批准号: 8703658
• 负责人: Ann Progulske-Fox
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-18 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703658
• 关键词: Accounting; Adherence; Animal Model; Arterial Fatty Streak; Arteries; Atherosclerosis; Bacteremia; Bacteria; Bacterial Adhesins; Binding Proteins; Biological Markers; Biological Models; Blood Vessels; Brain; Brain hemorrhage; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Communication; Cells; Cessation of life; Child; Collagen; Communicable Diseases; Complex; DNA Sequence; Data; Dental Care; Dental caries; Disease; Endocarditis; Endothelial Cells; Epidemiology; Eukaryotic Cell; Event; Fatal Outcome; Genes; Health; Heart Valves; Human; Incidence; Individual; Infection; Infectious Agent; Inflammatory; Invaded; Mediating; Molecular; Mouth Diseases; Mus; Oral; Oral cavity; Pathology; Pathway interactions; Patients; Personal Communication; Phenotype; Physiological; Play; Process; Reporting; Role; Rupture; Serotyping; Severities; Signal Transduction; Site; Streptococcus; Streptococcus mutans; Streptococcus rattus; Stroke; Testing; Tissues; Vascular Endothelial Cell; Virulence; Work; design; in vitro Model; insight; mouse model; oral infection; oral pathogen; oral streptococci; oral tissue; pathogen; trafficking

DESCRIPTION (provided by applicant): Streptococcus mutans (Sm) has long been recognized as a major pathogen of dental caries, the most common infectious disease in humans. What is much less appreciated is its role in extra-oral infections. Sm is an opportunistic pathogen frequently identified in human bacteremias and is an etiologic agent of infectious endocarditis (IE). IE, a valvular vegetation of the endothelial layer, is a serious cardiovascular disease with often fatal outcomes directly related to dental procedures. There is now strong evidence that Sm is involved in hemorrhagic stroke, which occurs when a blood vessel ruptures in the brain. Additionally, epidemiological and DNA sequencing evidence supports a contributing role of Sm to atherosclerosis. Atherosclerosis is a complex inflammatory disease afflicting medium and large sized arteries and is the leading cause of death in the USA. The commonality of these diseases is that they are diseases of the cardiovascular system. The ability of a pathogen to attach to and invade endothelial tissues has previously been shown to be required for virulence in IE and the ability to invade endothelial cells has been shown to correlate with endocardititis severity. We have previously reported that specific strains of Sm can invade human cardiovascular aortic endothelial cells (HCAEC). New data demonstrate that the HCAEC invasion phenotype correlates with the presence of a gene encoding a collagen binding protein, Cnm, and that deletion of cnm renders the strains unable to invade. Sm OMZ175, a strain that expresses Cnm, produces significant pathology compared to control mice in a mouse model of accelerated atherosclerosis. Intracellular pathogens have evolved multiple pathways and mechanisms to enter, traffic and survive within eukaryotic cells. Thus, the mode of entry plays a major role in determining bacterial fate. There are no reports about the cellular events that govern Sm entry into cells. Our overall hypothesis is that strains of Sm expressing Cnm, such as our model organism OMZ175, are able to adhere to, enter, and persist in HCAECs and that the mechanism of entry is critical to the trafficking and survival of Sm intracellularly. Our workig hypothesis to be tested in this proposed project is that invasive Sm enters endothelial cells using specific mechanisms and that Cnm plays a central role in this entry. Understanding the mechanisms that specific strains of a ubiquitous oral pathogen have acquired that expand its virulence to sites outside of the oral cavity would provide further insight into the molecular details of adhesin mediated streptococci interactions with its host. The specific aims of this application are 1) Determine the mechanism of entry of Sm into HCAEC and 2) Determine the contribution of Cnm in the entry process. Our own data and that of others indicate that invasive strains of Sm also invade oral cells and can be detected in predentate children. In addition, cnm has now been found in strains of S. sanguinis, S. suis and S. rattus. Therefore these studies will have significance beyond CVD pathology. In addition, this project would contribute information concerning the application of cnm as a biomarker for hypervirulent strains of Sm.

描述（由申请人提供）：变形链球菌（Streptococcus mutans, Sm）是人类最常见的感染性疾病——龋齿的主要病原体。人们很少认识到的是它在口腔外感染中的作用。Sm是人类细菌血症中常见的机会致病菌，是感染性心内膜炎（IE）的病原。IE是一种严重的心血管疾病，通常与牙科手术直接相关。现在有强有力的证据表明，Sm与出血性中风有关，这种中风发生在大脑血管破裂时。此外，流行病学和DNA测序证据支持Sm对动脉粥样硬化的促进作用。动脉粥样硬化是一种复杂的炎症性疾病，困扰着大中型动脉，是美国主要的死亡原因。这些疾病的共同点是它们都是心血管系统的疾病。病原体附着和侵入内皮组织的能力先前已被证明是IE毒性所必需的，并且侵入内皮细胞的能力已被证明与心内膜炎的严重程度相关。我们以前报道过特定的Sm菌株可以侵入人心血管主动脉内皮细胞（HCAEC）。新的数据表明，HCAEC侵袭表型与编码胶原结合蛋白Cnm的基因存在相关，而Cnm的缺失使菌株无法入侵。Sm OMZ175是一种表达Cnm的菌株，在加速动脉粥样硬化的小鼠模型中，与对照小鼠相比，产生了显著的病理变化。细胞内病原体已经进化出多种途径和机制来进入、运输和在真核细胞内生存。因此，进入方式在决定细菌命运方面起着重要作用。没有关于控制Sm进入细胞的细胞事件的报道。我们的总体假设是，表达Cnm的Sm菌株，如我们的模式生物OMZ175，能够粘附、进入并持续存在于hcaec中，并且进入机制对Sm在细胞内的运输和存活至关重要。我们在这个项目中要验证的工作假设是，侵袭性Sm通过特定的机制进入内皮细胞，而Cnm在这一进入中起着核心作用。了解一种普遍存在的口腔病原体的特定菌株已获得将其毒力扩展到口腔外的机制，将有助于进一步了解粘附素介导的链球菌与其宿主相互作用的分子细节。本应用的具体目的是：1)确定Sm进入HCAEC的机制；2)确定Cnm在进入过程中的贡献。我们自己的数据和其他人的数据表明，Sm的侵袭性菌株也侵入口腔细胞，可以在学龄前儿童中检测到。此外，cnm现已在血链球菌、猪链球菌和鼠链球菌菌株中发现。因此，这些研究将具有超越心血管疾病病理学的意义。此外，该项目将为cnm作为Sm高毒菌株的生物标记物的应用提供信息。