Mechanisms of vascular damage by systemic dissemination of the oral pathogen Porphyromonas gingivalis

Abstract

Several studies have shown a clear association between periodontal disease and increased risk of cardiovascular disease. Porphyromonas gingivalis (Pg), a key oral pathogen, and its cell surface-expressed gingipains, induce oedema in a zebrafish larvae infection model although the mechanism of these vascular effects is unknown. Here, we aimed to determine whether Pg-induced vascular damage is mediated by gingipains. In vitro, human endothelial cells from different vascular beds were invaded by wild-type (W83) but not gingipain-deficient (ΔK/R-ab) Pg. W83 infection resulted in increased endothelial permeability as well as decreased cell surface abundance of endothelial adhesion molecules PECAM-1 and VE-cadherin compared to infection with ΔK/R-ab. In agreement, when transgenic zebrafish larvae expressing fluorescently labelled PECAM-1 or VE-cadherin were systemically infected with W83 or ΔK/R-ab, a significant reduction in adhesion molecule fluorescence was observed specifically in endothelium proximal to W83 bacteria through a gingipain-dependent mechanism. Furthermore, this was associated with increased vascular permeability in vivo when assessed by dextran leakage microangiography. These data are the first to show that Pg directly mediates vascular damage in vivo by degrading PECAM-1 and VE-cadherin. Our data provide a molecular mechanism by which Pg might contribute to cardiovascular disease.

Deep Learning Reveals Key Immunosuppression Genes and Distinct Immunotypes in Periodontitis

“…PECAM1 is found to be a co-modulator of T-cell immunity (Huang et al, 2017) and a promoter of endothelial junctional integrity (Marelli-Berg et al, 2013). Periodontal pathogens, particularly P. gingivalis, can induce vascular damage through the degradation of PECAM1 (Yun et al, 2005;Farrugia et al, 2020). A protective effect of PECAM1 was also detected in transplant arteriosclerosis (Ensminger et al, 2002).…”

Oral Microbiota: A Major Player in the Diagnosis of Systemic Diseases

“…Moreover, polymicrobial infection with Pg, Td, Tf, and Fn is associated with accelerated atherosclerosis in vivo [100,101]. Recent studies showed that Pg is able to increase vascular permeability and cause vascular damages via, respectively, its outer membrane vesicles and surface-expressed gingipains in vitro and in vivo in a zebrafish model [102]. Also, Pussinen et al found that coronary heart disease is more common in people who have anti-Pg antibodies compared to those who do not, suggesting that periodontal infection or the host's response to anti-Pg infection could play a role in the pathogenicity of coronary heart disease [103,104].…”

“…They may also be an early sign of therapeutic escape or disease relapse. People suffering from IBD are characterized by dysbiotic oral and gut microbiota with a decrease in bacterial diversity, a decrease in the abundance of Firmicutes phylum, and an increase in the abundance of Proteobacteria and Bacteroidetes phylum [102,[177][178][179]. Recent studies showed that, compared to healthy people, these people also presented an oral dysbiosis and that periodontitis was significantly associated with IBD [180,181].…”

Periodontitis and Systemic Disorder—An Overview of Relation and Novel Treatment Modalities

“…As gingipains are proteolytic enzymes, they cause bacterial virulence by activating matrix metalloproteinases such as MMP-1, MMP-3, and MMP-95, and by degrading extracellular matrix host proteins such as collagen, fibronectin, and laminin. Gingipains also lead to increased vascular permeability and the degradation of complement factors [ 33 , 34 ].…”