Treponema denticola, complement regulatory proteins and periodontal disease

描述（由申请人提供）：牙周病会影响大多数人在他们生活中的某个阶段，其经济影响是巨大的。牙周炎是由宿主因素和正常菌群来源的多微生物感染共同引起的。当每个物种的数量失衡时，疾病就产生了。牙周病的一个诱因是密螺旋体（Td）。我们证明，Td通过一个11.5 kDa的Td脂蛋白（FhbB）结合补体调节蛋白，因子H样蛋白1 （FHL-1）。FhbB是唯一已知的由微生物病原体产生的特异性结合FHL-1而非FH的蛋白质。这种独特的结合特异性为了解FHL-1与Td结合的生物学原理提供了可能。除了补体调节作用外，FHL-1还具有重要的细胞粘附和细胞扩散活性。一些依赖锚定的细胞系已被证明与FHL-1基质结合。这种结合通过FHL-1的RGD基序发生，该基序位于一个称为短一致重复（SCR） 4的结构域。FHL-1也通过其RGD粘附受体识别序列与组织的细胞外基质（ECM）相互作用。我们的假设是，齿状霉FhbB蛋白与细胞或ECM锚定的FHL-1的结合在齿状霉发病机制的几个关键方面起着核心作用，包括粘附、生物膜形成、组织渗透和免疫逃逸。本文提出的研究填补了牙周病发病机制和口腔菌群结合FHL-1的生物学作用研究的重要空白，并将促进我们对牙周病发生和进展的分子机制的总体理解。该应用的具体目的是：1 .分析牙周病患者体内fhbB的表达和产生，评估抗fhbB抗体反应；2: FhbB参与FHL-1结合的分子决定因素的鉴定；3)分析FhbB和FHL-1结合通过等位基因交换诱变和互补在齿齿田鼠发病中的作用。一般描述：本应用研究了牙周病病原体的一种新的毒力机制。这些分析的结果将有助于制定新的牙周病预防和干预战略。

DESCRIPTION (provided by applicant): Periodontal disease will affect most individuals at some point in their life and its economic impact is enormous. Periodontitis results from a combination of host factors and a polymicrobial infection of normal flora origin. Disease results when an imbalance in numbers of each species develops. One contributor to periodontal disease is Treponema denticola (Td). We demonstrate that Td binds the complement regulatory protein, factor H like protein 1 (FHL-1) via an 11.5 kDa Td lipoprotein, designated, FhbB. FhbB is the only known protein produced by a microbial pathogen that specifically binds FHL-1 and not FH. This unique binding specificity provides possible insight into the biological rationale of FHL-1 binding by Td. In addition to its complement regulatory role, FHL-1 also has important cell adhesin and cell spreading activities. Several anchorage dependent cell lines have been demonstrated to bind to an FHL-1 matrix. The binding occurs through an RGD motif of FHL-1 that is located with a domain referred to as a short consensus repeat (SCR) 4. FHL-1 also interacts with the extracellular matrix (ECM) of tissue via this its RGD adhesion receptor recognition sequence. It is our hypothesis that the binding of cell or ECM anchored FHL-1 by the T. denticola FhbB protein plays a central role in several critical aspects of T. denticola pathogenesis including adherence, biofilm formation, tissue penetration and immune evasion. The studies proposed here fill an important niche in the study of T. denticola pathogenesis and of the biological role of FHL-1 binding by oral microflora and will advance our general understanding of the molecular mechanisms associated with the development and progression of periodontal disease. The Specific Aims of this application are: 1: Analysis of fhbB expression and production in the human host and assessment of the anti- FhbB antibody response during periodontal disease; 2: Identification of the molecular determinants of FhbB involved in FHL-1 binding; and 3) Analysis of the role of FhbB and FHL-1 binding in T. denticola pathogenesis through allelic exchange mutagenesis and complementation. General description: This application investigates a novel virulence mechanism employed by a causative agent of periodontal disease. The outcome of these analyses will allow for the development of new preventive and intervention strategies for periodontal disease.