Tricking the gatekeepers: subversion of host immune responses by Porphyromonas gingivalis

Periodontitis is characterized by a chronic inflammation of the tissues supporting the teeth eventually leading to tooth loss. An important characteristic of this widespread oral disease is the microbial dysbiosis that is initiated by the keystone pathogen Porphyromonas gingivalis. Interestingly, both periodontitis and P. gingivalis were previously associated with several major non-oral diseases, including rheumatoid arthritis and Alzheimer’s disease. P. gingivalis contributes to periodontal disease by producing several virulence factors, especially (i) the ‘P. gingivalis peptidyl-arginine deiminase’ (PPAD), which is an enzyme capable of removing positive charges from bacterial and human proteins, and (ii) aggressive proteolytic enzymes, known as gingipains, which degrade a wide array of host proteins. The aim of this PhD research project was to determine how P. gingivalis targets these virulence factors to human host cells, and how they contribute to disease development. The results show that the bacterium targets its virulence factors to human host cells both in a water-soluble state and in association with secreted outer membrane vesicles (OMVs). The OMVs were subsequently shown to coat and antagonize major human immune cells, the so-called neutrophils, which form the main frontline against P. gingivalis in the gum tissues of patients with periodontitis. In particular, PPAD was found to ‘neutralize’ the neutrophil immune defenses at several levels, whereas the gingipains were shown to degrade neutrophil-derived antibacterial proteins. Altogether, this PhD research shows that PPAD, gingipains and OMVs secreted by P. gingivalis are important potential targets for preventive and therapeutic approaches against periodontitis and associated diseases.