Oral Pathogens: Polymicrobial Virulence Interactions

描述：人类的主要多菌感染在临床上表现为牙周病，到50岁时，近一半的人受到这种疾病的困扰，并与定植于龈下沟的微生物生物膜的形成有关。所提出的致病机制是多种多样的，主要是由于由许多细菌分类群、病毒和真菌组成的复杂的微生物群落。然而，这些龈下微生物群中的某些一直与SOT和硬组织的渐进性破坏有关，这些组织已经被很好地记录在临床环境中发生(即牙周炎)。不同的体内和体外研究表明，某些物种在龈下生态中的优势是微生物协同和拮抗关系的结果。这些都与可供定居的表面的性质、可用营养物质和群落内存在的生理“食物网”有关。分子微生物学研究描述了近500种可以栖息在这一生态位中的细菌，尽管在进行组织破坏的部位描述了几个特定的微生物复合体。在大多数成人牙周炎患者中发现的一种主要联合体包括牙龈卟啉单胞菌、Forsythens[类杆菌]和齿密螺旋体。这一联合体与疾病的相关性被认为是组成物种之间的协同生理、逃避寄主和/或组织破坏能力的结果。这个R01应用程序的目的是测试这样一个假设，即这个多菌联合体包括一个协同增加组织破坏性宿主反应的“毒力网”，而联合体不那么有效地修改宿主免疫反应。利用动物模型系统提出了三个特定的目标来验证这一假说：(1)在活体颅骨骨吸收模型中确定牙龈假单胞菌、连翘支原体和齿轮虫的分子间协同毒力效应，(2)确定对多微生物感染的获得性体液免疫反应的特征以及这种反应调节体内颅骨吸收的能力，以及(3)确定对多微生物免疫的主动体液免疫反应的特征和这种反应调节骨吸收的能力。这项研究的长期目标将是记录微生物的相互作用、毒力协同作用，表征获得性和主动性免疫反应，并将这些与组织破坏和骨吸收的变化联系起来。这一应用的意义在于，临床观察表明，口腔微生物能够转移到循环中，系统地表现为心内膜炎、脑/肾/肺和腹部感染，并导致糖尿病、冠状动脉疾病、骨质疏松症、肥胖和早产的风险。因此，宿主对这些慢性感染的反应必须被视为对一般健康至关重要。

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.