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.
Periodontitis is a prevalent oral disease that can ultimately lead to tooth loss. In this project we shall study the means by which one of major causative agents of periodontitis establishes itself in the mouth. This has the potential to identify therapeutic targets which in turn can be included in oral health products designed to mitigate the severity of periodontitis.
| Lee, Jae Y; Miller, Daniel P; Wu, Leng et al. (2018) Maturation of the Mfa1 Fimbriae in the Oral Pathogen Porphyromonas gingivalis. Front Cell Infect Microbiol 8:137 |
