Characterization of P. gingivalis minor fimbrial accessory proteins

 描述（由申请人提供）：牙周炎是一种慢性炎症性疾病，在美国，35岁以上的成年人中约有一半受到影响。临床结果包括牙周组织损伤和牙槽骨丢失，最终导致牙齿脱落。牙龈卟啉单胞菌（Porphyromonas gingivalis）是成人牙周炎的主要致病菌，具有多种毒力因子，能在牙周区定植，对宿主免疫产生抗性，并介导牙周组织的破坏。牙龈卟啉单胞菌通过与常见的口腔细菌如S. gordonii。牙龈卟啉单胞菌与S. gordonii感染是由牙龈卟啉单胞菌的短/小菌毛介导的，其与SspA/B链球菌表面蛋白相互作用。牙龈卟啉单胞菌和牙龈卟啉单胞菌群落。戈登氏菌在牙槽骨丢失的小鼠模型中比单独的任一种生物体致病性更高。次要/短菌毛由Mfa 1结构亚基组成，mfa 1基因是包含mfa 1、mfa 2、mfa 3、pgn 0290和pgn 0291的簇的一部分。mfa 2是一种锚定和长度调节蛋白。Mfa 3是位于菌毛尖端的辅助蛋白，并且是将来自pgn 0290和pgn 0291的蛋白（我们分别命名为Mfa 4和Mfa 5）整合到菌毛结构中所必需的。然而，除此之外，关于蛋白质相互作用、超分子结构和Mfa 3、4和5的功能知之甚少。我们提出了3个具体的目标来解决这些问题：确定Mfa 4和Mfa 5在Mfa菌毛上的位置，并表征Mfa 3，4和5之间的结合相互作用;确定Mfa 3，Mfa 4和Mfa 5在牙龈卟啉单胞菌与S. gordonii;并确定Mfa 3、Mfa 4和Mfa 5在体内多微生物协同作用中的作用。本研究的结果将为牙龈卟啉单胞菌的一个重要毒力因子提供新的结构和功能细节。这有可能导致设计新的治疗剂以靶向牙龈卟啉单胞菌定殖的效应分子，并防止牙龈卟啉单胞菌积累成多微生物协同群落。

 DESCRIPTION (provided by applicant): Periodontitis is a chronic inflammatory disease affecting around half the adults over 35 in the United States. Clinical outcomes include damage to periodontal tissues and alveolar bone loss, with eventually exfoliation of the teeth. Porphyromonas gingivalis is a keystone pathogen in adult periodontitis, and the organism possesses a number of virulence factors that enable colonization of the periodontal area, confer resistance to host immunity, and mediate destruction of periodontal tissues. P. gingivalis colonization of antecedent oral communities is facilitated by binding to common oral bacteria such as S. gordonii. Attachment of P. gingivalis to S. gordonii is mediated by the short/minor fimbriae of P. gingivalis which interact with the SspA/B streptococcal surface proteins. Communities of P. gingivalis and S. gordonii are more pathogenic in a mouse model of alveolar bone loss compared to either organism alone. The minor/short fimbriae are comprised of the Mfa1 structural subunit, and the mfa1 gene is part of a cluster that contains mfa1, mfa2, mfa3, pgn0290, and pgn0291. Mfa2 is an anchoring and length regulating protein. Mfa3 is an accessory protein localized to the fimbrial tip and necessary for the integration of proteins derived from pgn0290 and pgn0291 (which we designate Mfa4 and Mfa5 respectively) into the fimbrial structure. Beyond this, however, little is known regarding protein interactions, supramolecular structure, and the functions of Mfa3, 4 and 5. We propose 3 specific aims to address these topics: To determine the location of Mfa4 and Mfa5 on the Mfa fimbriae and characterize the binding interactions among Mfa3, 4 and 5; to determine the role of Mfa3, Mfa4, and Mfa5 in P. gingivalis co-adhesion to S. gordonii; and to determine the role of Mfa3, Mfa4 and Mfa5 in polymicrobial synergy in vivo. The findings from this study will provide novel structural and functional detail of an important virulence factor of P. gingivalis. This has the potential to lead to the design of new therapeutics to target the effector molecules of P. gingivalis colonization, and prevent the accumulation of P. gingivalis into polymicrobially synergistic communities.