Porphyromonas gingivalis bacteremia increases the permeability of the blood-brain barrier via the Mfsd2a/Caveolin-1 mediated transcytosis pathway / 国际口腔科学杂志·英文版

Bacteremia induced by periodontal infection is an important factor for periodontitis to threaten general health. P. gingivalis DNA/virulence factors have been found in the brain tissues from patients with Alzheimer's disease (AD). The blood-brain barrier (BBB) is essential for keeping toxic substances from entering brain tissues. However, the effect of P. gingivalis bacteremia on BBB permeability and its underlying mechanism remains unclear. In the present study, rats were injected by tail vein with P. gingivalis three times a week for eight weeks to induce bacteremia. An in vitro BBB model infected with P. gingivalis was also established. We found that the infiltration of Evans blue dye and Albumin protein deposition in the rat brain tissues were increased in the rat brain tissues with P. gingivalis bacteremia and P. gingivalis could pass through the in vitro BBB model. Caveolae were detected after P. gingivalis infection in BMECs both in vivo and in vitro. Caveolin-1 (Cav-1) expression was enhanced after P. gingivalis infection. Downregulation of Cav-1 rescued P. gingivalis-enhanced BMECs permeability. We further found P. gingivalis-gingipain could be colocalized with Cav-1 and the strong hydrogen bonding between Cav-1 and arg-specific-gingipain (RgpA) were detected. Moreover, P. gingivalis significantly inhibited the major facilitator superfamily domain containing 2a (Mfsd2a) expression. Mfsd2a overexpression reversed P. gingivalis-increased BMECs permeability and Cav-1 expression. These results revealed that Mfsd2a/Cav-1 mediated transcytosis is a key pathway governing BBB BMECs permeability induced by P. gingivalis, which may contribute to P. gingivalis/virulence factors entrance and the subsequent neurological impairments.

Porphyromonas gingivalis, a periodontal pathogen, impairs post-infarcted myocardium by inhibiting autophagosome-lysosome fusion / 国际口腔科学杂志·英文版

While several previous studies have indicated the link between periodontal disease (PD) and myocardial infarction (MI), the underlying mechanisms remain unclear. Autophagy, a cellular quality control process that is activated in several diseases, including heart failure, can be suppressed by Porphyromonas gingivalis (P.g.). However, it is uncertain whether autophagy impairment by periodontal pathogens stimulates the development of cardiac dysfunction after MI. Thus, this study aimed to investigate the relationship between PD and the development of MI while focusing on the role of autophagy. Neonatal rat cardiomyocytes (NRCMs) and MI model mice were inoculated with wild-type P.g. or gingipain-deficient P.g. to assess the effect of autophagy inhibition by P.g. Wild-type P.g.-inoculated NRCMs had lower cell viability than those inoculated with gingipain-deficient P.g. This study also revealed that gingipains can cleave vesicle-associated membrane protein 8 (VAMP8), a protein involved in lysosomal sensitive factor attachment protein receptors (SNAREs), at the 47th lysine residue, thereby inhibiting autophagy. Wild-type P.g.-inoculated MI model mice were more susceptible to cardiac rupture, with lower survival rates and autophagy activity than gingipain-deficient P.g.-inoculated MI model mice. After inoculating genetically modified MI model mice (VAMP8-K47A) with wild-type P.g., they exhibited significantly increased autophagy activation compared with the MI model mice inoculated with wild-type P.g., which suppressed cardiac rupture and enhanced overall survival rates. These findings suggest that gingipains, which are virulence factors of P.g., impair the infarcted myocardium by cleaving VAMP8 and disrupting autophagy. This study confirms the strong association between PD and MI and provides new insights into the potential role of autophagy in this relationship.

The virulence system of Porphyromonas gingivalis: Genes, mechanism and potential role of gingipains inhibitors

ABSTRACT@#The oral microbiome comprises several hundreds of bacterial species that contribute to periodontitis, the most complex polymicrobial inflammatory disorder. Porphyromonas gingivalis is a prominent periodontitis pathogen that produces gingipains as a major virulent factor. Gingipain facilitates P. gingivalis survival, pathogenicity, and growth. Several genes were identified to have a role in the regulating of P. gingivalis pathogenesis. Studies suggest that gingipains inhibition is key for the successful treatment of periodontitis. As of now, several gingipain inhibitors have been developed, some exhibit high inhibition activity against gingipains. However, most inhibitors offer unknown toxicity and undesirable side effects. Hence, the development of highly potent and safe gingipain inhibitor is a major concern for periodontitis treatment. The present review highlights the connectivity between P. gingivalis, virulent factors, and its gene, periodontitis, and gingipain inhibitors. Development of gingipains inhibitors would not only treat periodontitis but would also assist in the treatment of other associated systemic diseases, for example: rheumatoid arthritis, cardiovascular diseases, diabetes, and Alzheimer's disease.