UKY DENTAL COBRE: ORAL INFECTIONS: HOST RESPONSES TO POLYMICROBIAL INFECTIONS

人类的主要多菌感染在临床上表现为牙周病，到50岁时，近1/2的人会受到这种疾病的困扰，这与定植于龈上和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软硬组织的渐进性破坏有关，这种破坏已被很好地记录在临床环境中(即牙周炎)。分子微生物学研究描述了近500种细菌可以栖息在这个生态位上。在大多数成人牙周炎患者中发现的一种主要致病联合体由牙龈假单胞菌、连翘支原体和齿状支原体组成。这种联合体与疾病的相关性被认为是生理、宿主逃避和/或组织协同作用的结果 组成物种之间的破坏性能力。同样，细菌协会在健康中被认为是“早期生物膜殖民者”(例如。S.gordonii、A.nesnudii、V.非典型)和“桥接种”(如：已被鉴定为在病原菌生物被膜的建立过程中起关键作用的病原菌有核盘藻(F.nuatum)、稻瘟菌属(C.ochraceae)、罗氏盘菌(P.loescheii)。此R01应用程序的目标是测试一种假设，即“致病多菌联合体”包含一个“毒力网”，该网独特地协同增加组织破坏性宿主反应，并且宿主免疫反应被该联合体修改为不那么有效。利用动物模型系统对这一假说提出了四个具体的目标：(1)确定致病菌根霉菌、金黄色葡萄球菌和金黄色葡萄球菌的分子间协同毒力效应。 (2)确定对多细菌感染的获得性免疫反应的特征以及这种反应调节转录组和骨吸收反应的能力，(3)确定对多细菌免疫的主动免疫反应的特征以及这种反应调节转录组和骨吸收反应的能力，以及(4)确定在活体颅骨吸收模型中口腔常见菌，S.gordonii，A.nesnudii，V.atypica，F.nuatum，C.ochracea和P.loescheii的毒力效应。长期目标是记录对病原性和共生性潜伏杆菌挑战的转录组反应，毒力协同作用，表征获得性和主动性免疫反应，并将这些反应与组织丢失和骨吸收联系起来。这项资助的意义在于了解口腔中发生的宿主与细菌的相互作用。临床观察表明，这些相互作用的最终结果是对系统性疾病及其后遗症产生影响。因此，宿主对慢性感染的反应必须被认为是调节感染和维持一般健康的关键。

The predominant polymicrobic infection of mankind is expressed clinically as periodontal disease, which afflicts nearly 1/2 of the population by 50 years of age, and is related to development of a microbial biofilm colonizing the supra- and 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 soft and hard tissue that has been well documented to occur in clinical settings (i.e.periodontitis). Molecular microbiologic studies have described nearly 500 species of bacteria that can inhabit this ecololgical niche. A predominant pathogenic consortium identified in a majority of adult periodontitis patients consists of P. gingivalis, T. forsythensis, and T. 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. Similarly, bacterial consortia identified in health as "early biofilm colonizers" (eg. S. gordonii, A. naeslundii, V. atypical) and "bridging species" (eg. F. nucleatum, C. ochraceae, P. loescheii) have been identified to be crucial in establishment of a pathogenic biofilm. The objectives of this R01 application are to test an hypothesis that a "pathogenic polybacterial consortium" comprises a "virulence web" that uniquely synergizes to increase tissue destructive host responses, and that host immune responses are modified by the consortium to be less effective. Four specific aims are proposed using an animal model system to test this hypothesis: (1) To determine molecular interbacterial synergistic virulence effects of a pathogenic consortium P. gingivalis, T. forsythensis, and T. denticola in an in vivo calvarial bone resorption model, (2) To determine the characteristics of acquired immune responses to a polybacterial infection and the ability of this response to modulate transcriptome & bone resorption responses, (3) To determine the characteristics of active immune responses to polybacterial immunization and the ability of this response to modulate transcriptome & bone resorption responses, and (4) To determine virulence effects of eommensal oral bacteria, S. gordonii, A. naeslundii, V. atypica, F. nucleatum, C. ochracea, and P. loescheii, in an in vivo calvarial bone resorption model. The long-range goals are to document transcriptome responses to pathogenicand commensal potybacterial challenges, virulence synergisms, characterize acquired and active immune responses, and relate these to tissue loss and bone resorption. The significance of this grant is to understand the host-bacterial interactions that occur in the oral cavity. The net result of these interactions have been suggested by clinical observations to have an effect on systemic diseases and their sequelae. Consequently, the host response to the chronic infections must be considered as critical in modulating infection and maintaining general health.