The Keystone‐Pathogen Hypothesis Updated: The Role of Porphyromonas gingivalis in Periodontitis

ABSTRACT We have previously described Porphyromonas gingivalis as a keystone pathogen due to its critical contribution to the development of periodontitis. Healthy periodontal tissue contains an active innate host defense system made in response to commensal bacterial colonization that facilitates an orchestrated expression of protective host mediators. We designated P. gingivalis as a keystone pathogen since it impairs host defense, leading to the overgrowth of oral commensal bacteria, altering a protective host surveillance response to a destructive, increased host inflammatory response. In addition, P. gingivalis uncouples inflammation from bactericidal activity, which manipulates the host inflammatory response in a way that promotes bone loss but not bacterial clearance. In this review, we update the keystone hypothesis by summarizing recent key fields of research that enhance our understanding of the keystone properties of this organism. For example, the last decade has witnessed significant progress in the characterization of the mechanism of export of some of the critical virulence determinants of P. gingivalis via the type IX secretion system (T9SS). These include, but are not limited to, the gingipain proteases, hemagglutinins, and numerous other potential virulence factors that require further characterization. As an example, the secretion of P. gingivalis peptidylarginine deiminase (PPAD), which has been shown to neutralize human innate immune defenses, is exported via the T9SS. In addition, outer membrane vesicles (OMV) are increasingly recognized as effective long‐distance vehicles of P. gingivalis virulence determinants to the external environment. Furthermore, OMVs have been shown to provide a novel delivery system for lipid A structures attached to the two lipopolysaccharides produced by this bacterium: O‐LPS and A‐LPS. Lipid A modifications by P. gingivalis represent a key patho‐adaptation by modulating the host immuno‐inflammatory response and providing protection from bacterial killing. Critically, it is also recognized that the full expression of the P. gingivalis keystone phenotype is strain‐dependent and subject to environmental control, both of which may contribute to an individual's susceptibility to disease. These studies further validate and confirm the key contribution of P. gingivalis to the transition from periodontal health to disease.