Oral Pathogens: Polymicrobial Virulence Interactions

描述：人类主要的多微生物感染在临床上表现为牙周病，在50岁之前折磨近一半的人口，并且与牙龈下沟定植的微生物生物膜的发展有关。提出的发病机制是多种多样的，在很大程度上是由于复杂的微生物群落组成的众多细菌分类群，病毒和真菌。尽管如此，某些龈下微生物群落始终与牙周炎和硬组织的渐进式破坏相关，这在临床环境（即牙周炎）中已得到充分记录。各种体内和体外研究表明，牙龈下生态中特定物种的优势源于微生物的协同作用和拮抗关系。这些都与群落中存在的可利用表面、可用营养物质和生理“食物网”的性质有关。分子微生物学研究已经描述了近500种可以居住在这个生态位的细菌，尽管一些特定的微生物复合物已经在组织破坏的地方被描述。在大多数成人牙周炎患者中发现的主要菌落包括牙龈卟啉单胞菌、连翘拟杆菌和牙密螺旋体。这种联合体与疾病的相关性被认为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。本R01申请的目的是验证一种假设，即这种多微生物联合体包括一个“毒力网”，协同增加组织破坏性宿主反应，而联合体对宿主免疫反应的影响较小。提出了三个具体目标，使用动物模型系统来验证这一假设：(1)在体内颅骨骨吸收模型中确定牙龈假单胞菌、forsythensis假单胞菌和齿状假单胞菌的分子细菌间协同毒力效应；(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骨吸收的能力；(3)确定对多微生物免疫的主动体液免疫反应的特征以及这种反应调节骨吸收的能力。本研究的长期目标将是记录微生物相互作用、毒力协同作用、获得性和主动免疫反应的特征，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有能力转移到循环系统，并表现为心内膜炎、脑/肾/肺和腹腔内感染，并增加糖尿病、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.