Oral Pathogens: Polymicrobial Virulence Interactions

口腔病原体：多种微生物毒力相互作用

• 批准号: 6999788
• 负责人: Kesavalu Naidu Lakshmyya
• 金额: $ 22.28万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2006-10-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999788
• 关键词: Bacteroides gingivalis; Treponema; bacterial cytopathogenic effect; bacterial vaccines; chemokine receptor; chronic disease /disorder; cytokine receptors; drug interactions; enzyme linked immunosorbent assay; gene induction /repression; host organism interaction; humoral immunity; immune response; leukocyte activation /transformation; microarray technology; microorganism growth; microorganism interaction; oral bacteria; pathologic bone resorption; pathologic process; periodontitis; periodontium disorder; polymerase chain reaction; secondary infection; transcription factor; virulence

DESCRIPTION: The predominant polymicrobic infection of mankind is expressed clinically as periodontal disease, which afflicts nearly one-half of the population by 50 years of age, and is related to development of a microbial biofilm colonizing the subgingival sulcus. The suggested mechanisms of pathogenesis are varied, in most part due to the complex microbial community consisting of numerous bacterial taxa, viruses, and fungi. Nevertheless, certain of these subgingival microbial consortia are consistently correlated with a progressive destruction of sot_ and hard tissue that have been well documented to occur in clinical settings (i.e., periodontitis). Various in vivo and in vitro investigations have suggested that the dominance of selected species in the subgingival ecology results from both microbial synergistic and antagonistic relationships. These have been linked to the nature of available surfaces for colonization, available nutrients, and physiologic "food webs" that exists within the community. Molecular microbiologic studies have described nearly 500 species of bacteria that can inhabit this ecological niche, although several specific microbial complexes have been described at sites of progressing tissue destruction. A predominant consortia identified in a majority of adult periodontitis patients consists of Porphyromonas gingivalis, TannereIla forsythensis [Bacteroides forsythus], and Treponema denticola. The correlation of this consortium with disease has been proposed to result from synergistic physiological, host evasion, and/or tissue destructive capabilities among the component species. The objectives of this R01 application are to test a hypothesis that this polymicrobic consortium comprises a "virulence web" that synergistically increases tissue destructive host responses, and the consortia to be less effective modify that host immune responses. Three Specific Aims are proposed using an animal model system to test this hypothesis: (1) To determine molecular interbacterial synergistic virulence effects of P. gingivalis, T. forsythensis, and T denticola in an in vivo calvarial bone resorption model, (2) To determine the characteristics of acquired humoral immune responses to a polymicrobial infection and the ability of this response to modulate in vivo calvarial bone resorption, and (3) To determine the characteristics of active humoral immune responses to polymicrobial immunization and ability of this response to modulate bone resorption. The long-range goals from this study will be to document microbial interactions, virulence synergisms, characterize both acquired and active immune responses, and relate these to alterations in tissue destruction and bone resorption. The significance of this application is that clinical observations have shown the ability of oral microorganisms to translocate into the circulation and manifest systemically as endocarditis, brain/kidney/lung, and intra-abdominal infections and contributing to risks of diabetes, coronary artery disease, osteoporosis, obesity, and preterm birth. Consequently, the host response to these chronic infections must be considered as critical to general health.

描述：人类主要的多种微生物感染在临床上表现为牙周病，近一半的 50 岁以上人口患有牙周病，并且与龈下沟内微生物生物膜的形成有关。所提出的发病机制各不相同，大部分是由于由众多细菌类群、病毒和真菌组成的复杂微生物群落所致。然而，某些龈下微生物群始终与软组织和硬组织的渐进性破坏相关，这些破坏已被充分记录在临床环境中发生（即牙周炎）。各种体内和体外研究表明，选定物种在龈下生态中的主导地位是微生物协同和拮抗关系的结果。这些与可用于定植的表面的性质、可用的营养物质以及群落内存在的生理“食物网”有关。分子微生物学研究已经描述了近 500 种细菌可以栖息在这个生态位中，尽管在正在进行的组织破坏部位已经描述了几种特定的微生物复合体。在大多数成人牙周炎患者中发现的主要菌群包括牙龈卟啉单胞菌、福赛拟杆菌和齿垢密螺旋体。已提出该联合体与疾病的相关性是由于组成物种之间的协同生理、宿主逃避和/或组织破坏能力造成的。该 R01 应用的目的是测试一个假设，即该多微生物群落包含协同增强组织破坏性宿主反应的“毒力网”，并且该群落不太有效地改变宿主免疫反应。提出了三个具体目标，使用动物模型系统来检验这一假设：(1) 在体内颅骨骨吸收模型中确定牙龈卟啉单胞菌、福赛菌和齿状杆菌的分子细菌间协同毒力效应，(2)确定对多种微生物感染的获得性体液免疫反应的特征以及该反应调节体内颅骨骨吸收的能力，以及（3）确定活性体液免疫反应的特征对多种微生物免疫的体液免疫反应以及该反应调节骨吸收的能力。这项研究的长期目标是记录微生物相互作用、毒力协同作用、表征获得性和主动免疫反应，并将这些与组织破坏和骨吸收的变化联系起来。该应用的意义在于，临床观察表明口腔微生物能够转移到循环系统中，并全身表现为心内膜炎、脑/肾/肺和腹内感染，并导致糖尿病、冠状动脉疾病、骨质疏松症的风险、肥胖和早产。因此，宿主对这些慢性感染的反应必须被视为对整体健康至关重要。