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Porphyromonas gingivalis is a member of the dysbiotic oral microbiome and a “keystone pathogen” that causes severe periodontal disease, which is among the most prevalent infectious diseases. Part of the virulence factors secreted by P. gingivalis are the essential cysteine peptidases gingipain K (Kgp) and R (RgpA and RgpB), which account for 85% of the extracellular proteolytic activity of the pathogen and are thus prime targets for inhibition. We report the high-resolution (1.20 Å) complex structure of Kgp with KYT-36, a peptide-derived, potent, bioavailable and highly selective inhibitor, which is widely used for studies in vitro , in cells and in vivo . Sub-nanomolar inhibition of Kgp is achieved by tight binding to the active-site cleft, which is covered for its sub-sites S 3 through S 1 ’ under establishment of nine hydrophobic interactions, 14 hydrogen bonds and one salt bridge. In addition, an inhibitor carbonyl carbon that mimics the scissile carbonyl of substrates is pyramidalized and just 2.02 Å away from the catalytic nucleophile of Kgp, C 477 Sγ. Thus, the crystal structure emulates a reaction intermediate of the first nucleophilic attack during catalysis of cysteine peptidases. The present study sets the pace for the development of tailored next-generation drugs to tackle P. gingivalis .

Cognitive impairment (CI) is a common complication of the non-motor symptoms in Parkinson’s disease (PD), including PD with mild cognitive impairment (PD-MCI) and PD dementia. Recent studies reported the oral dysbiosis in PD and CI, respectively. Porphyromonas gingivalis ( P. gingivalis ), a pathogen of oral dysbiosis, plays an important role in PD, whose lysine-gingipain (Kgp) could lead to AD-type pathologies. No previous study investigated the composition of oral microbiota and role of P. gingivalis in PD-MCI. This study aimed to investigate the differences of oral microbiota composition, P. gingivalis copy number, and Kgp genotypes among PD-MCI, PD with normal cognition (PD-NC) and periodontal status-matched control (PC) groups. The oral bacteria composition, the copy number of P. gingivalis , and the Kgp genotypes in gingival crevicular fluid from PD-MCI, PD-NC, and PC were analyzed using 16S ribosomal RNA sequencing, quantitative real-time PCR, and MseI restriction. We found that the structures of oral microbiota in PD-MCI group were significantly different compared to that in PD-NC and PC group. The relative abundances of Prevotella , Lactobacillus , Megasphaera , Atopobium , and Howardella were negatively correlated with cognitive score. Moreover, there was a significant difference of Kgp genotypes among the three groups. The predominant Kgp genotypes of P. gingivalis in the PD-MCI group were primarily Kgp II, whereas in the PD-NC group, it was mainly Kgp I. The Kgp II correlated with lower MMSE and MoCA scores, which suggested that Kgp genotypes II is related to cognitive impairment in PD.

Periodontal pathogen Porphyromonas gingivalis ( P. gingivalis ) is believed to possess immune evasion capabilities, but it remains unclear whether this immune evasion is related to host gene alternative splicing (AS). In this study, RNA-sequencing revealed significant changes in both AS landscape and transcriptomic profile of macrophages following P. gingivalis infection with/without knockout of gingipain (a unique toxic protease of P. gingivalis ). P. gingivalis infection increased the PD-L1 transcripts expression and selectively upregulated a specific coding isoform that more effectively binds to PD-1 on T cells, thereby inhibiting immune function. Biological experiments also detected AS switch of PD-L1 in P. gingivalis -infected or gingipain-treated macrophages. AlphaFold 3 predictions indicated that the protein docking compatibility between PD-1 and P. gingivalis -upregulated PD-L1 isoform was over 80% higher than another coding isoform. These findings suggest that P. gingivalis employs gingipain to modulate the AS of PD-L1, facilitating immune evasion.

and its inflammagens are associated with a number of systemic diseases, such as cardiovascular disease and type 2 diabetes (T2DM). The proteases, gingipains, have also recently been identified in the brains of Alzheimer's disease patients and in the blood of Parkinson's disease patients. Bacterial inflammagens, including lipopolysaccharides (LPSs) and various proteases in circulation, may drive systemic inflammation. Here, we investigate the effects of the bacterial products LPS from and , and also the gingipain [recombinant gingipain R1 (RgpA)], on clot architecture and clot formation in whole blood and plasma from healthy individuals, as well as in purified fibrinogen models. Structural analysis of clots was performed using confocal microscopy, scanning electron microscopy, and AFM-Raman imaging. We use thromboelastography® (TEG®) and rheometry to compare the static and dynamic mechanical properties of clots. We found that these inflammagens may interact with fibrin(ogen) and this interaction causes anomalous blood clotting. These techniques, in combination, provide insight into the effects of these bacterial products on cardiovascular health, and particularly clot structure and mechanics.

Periodontitis (PD) is a chronic inflammatory disease of the gingiva, with a high prevalence. Clinical reports indicate the significant role of PD in the development of comorbidities, including Herpesviridae infections; however, the molecular basis of this phenomenon has not yet been described. In our work, we uncovered a novel molecular mechanism by which the interferon-dependent antiviral response is tailored by the cysteine protease of P. gingivalis —Kgp. Using gingival keratinocytes and a model of human gingiva, we have demonstrated that lysin-specific gingipain attenuates the antiviral response and promotes the propagation of herpes simplex virus-1, which is one of the most frequently identified viruses in patients suffering from PD. These findings expand our knowledge of the mechanisms underlying polymicrobial infections and may provide a basis for considering PD as a gateway to viral infection.

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.

Periodontitis and oral pathogenic bacteria can contribute to the development of rheumatoid arthritis (RA). A connection between serum antibodies to ( ) and RA has been established, but data on saliva antibodies to in RA are lacking. We evaluated antibodies to in serum and saliva in two Swedish RA studies as well as their association with RA, periodontitis, antibodies to citrullinated proteins (ACPA), and RA disease activity. The SARA (secretory antibodies in RA) study includes 196 patients with RA and 101 healthy controls. The Karlskrona RA study includes 132 patients with RA ≥ 61 years of age, who underwent dental examination. Serum Immunoglobulin G (IgG) and Immunoglobulin A (IgA) antibodies and saliva IgA antibodies to the -specific Arg-specific gingipain B (RgpB) were measured in patients with RA and controls. The level of saliva IgA anti-RgpB antibodies was significantly higher among patients with RA than among healthy controls in multivariate analysis adjusted for age, gender, smoking, and IgG ACPA (p = 0.022). Saliva IgA anti-RgpB antibodies were associated with RA disease activity in multivariate analysis (p = 0.036). Anti-RgpB antibodies were not associated with periodontitis or serum IgG ACPA. Patients with RA had higher levels of saliva IgA anti-RgpB antibodies than healthy controls. Saliva IgA anti-RgpB antibodies may be associated with RA disease activity but were not associated with periodontitis or serum IgG ACPA. Our results indicate a local production of IgA anti-RgpB in the salivary glands that is not accompanied by systemic antibody production.

Gingipains are virulence factors released by that contribute to periodontal destruction by disrupting bone metabolism. This study aimed to evaluate the dual effects of gingipains on bone metabolism by examining their impact on osteogenesis and osteoclastogenesis, hypothesizing that gingipains regulate these processes via direct and exosomal pathways involving microRNA signaling. Clinical samples of gingival crevicular fluid, subgingival plaque, and gingival tissues were collected from 15 patients with stage III-IV periodontitis and 15 healthy controls. The effects of gingipains on bone marrow mesenchymal stem cells (BMSCs) and RAW264.7 macrophages were assessed using cell proliferation assays, qPCR, western blot, microarray analysis, and dual-luciferase reporter assays. A rat periodontitis model was used to validate the findings . Periodontitis patients exhibited elevated levels of lysine- and arginine-specific gingipains, C5a, and RANKL (p < 0.05). Gingipains inhibited BMSCs proliferation and osteogenic differentiation in a dose-dependent manner while promoting osteoclastogenesis in RAW264.7 macrophages through BMSCs-derived exosomes. Gingipains reduced the levels of miR-146a-5p in exosomes, which enhanced osteoclast differentiation through the miR-146a-5p/TRAF6 signaling pathway. Animal models confirmed that gingipains aggravated alveolar bone loss, which was mitigated by miR-146a-5p overexpression. Gingipains disrupt bone metabolism by inhibiting BMSCs osteogenesis and promoting osteoclastogenesis through communication via exosomes. Targeting miR-146a-5p offers a potential therapeutic approach to counter gingipain-induced periodontal destruction.

Porphyromonas gingivalis ( P. gingivalis ) is a keystone pathogen in periodontitis. However, several clinical studies have revealed an enrichment of P. gingivalis in the stool samples and colorectal mucosa of colorectal cancer patients. Thus, the goal of this study was to determine whether P. gingivalis can promote colorectal cancer progression in vitro . We established an acute infection model (24 h, multiplicity of infection =100) of P. gingivalis invasion of colorectal cancer cells to study the alterations induced by P. gingivalis in the proliferation and cell cycle of colorectal cancer cells. We observed that P. gingivalis can adhere and invade host cells a few hours after infection. Once invaded, P. gingivalis significantly promoted colorectal cancer cell proliferation, and the percentage of S phase cells was increased in the cell cycle assay. However, KDP136, a gingipain-deficient mutant of P. gingivalis 33277, showed a decreased ability to promote colorectal cancer cell proliferation, indicating that gingipain is associated with colorectal cancer cell proliferation. Furthermore, we extracted RNA from colorectal cancer cells for high-throughput sequencing analysis and reconfirmed the results by quantitative polymerase chain reaction and western blot analyses. The results suggested that the MAPK/ERK signaling pathway is significantly activated by P. gingivalis , while these changes were not observed for KDP136. In conclusion, P. gingivalis can invade cells and promote the proliferation of colorectal cancer cells by activating the MAPK/ERK signaling pathway. Gingipain is an essential virulence factor in this interaction.

Periodontitis is associated with rheumatoid arthritis (RA). One hypothesis posits that this connection arises from the formation of autoantibodies against citrullinated proteins (ACPA) in inflamed gums, possibly triggered by . We previously demonstrated an increased antibody response to arginine gingipains (anti-Rgp IgG), not only in individuals with severe periodontitis compared to controls, but in RA versus controls, with an association to ACPA. In the present study, we set out to further explore the relationship between anti-Rgp IgG, ACPA and periodontitis, including clinical periodontal parameters, in the large and well-characterized PerioGene North case-control study. We measured serum levels of anti-Rgp and ACPA IgG by enzyme-linked immunosorbent assay (ELISA), in 478 patients with periodontitis and 509 periodontally healthy controls within PerioGene North. Subsequently, anti-Rgp IgG levels and ACPA status were analysed in relation to periodontitis and clinical periodontal parameters. Serum anti-Rgp IgG levels were elevated in cases versus controls (p< 0.001). However, receiver operating characteristic (ROC) curve analysis revealed that anti-Rgp IgG could not efficiently discriminate cases from controls (AUC= 0.63; 95% CI: 0.60 - 0.66). Among cases, increased anti-Rgp IgG levels associated with high periodontal inflammation and advanced alveolar bone loss (p<0.001 for both). An ACPA response was detected in 15 (3.1%) cases and 6 (1.2%) controls (p=0.033), but no association to periodontitis was evident after adjustment for age and smoking and anti-Rgp IgG levels did not differ between ACPA-positive and ACPA-negative individuals. We show that anti-Rgp IgG identifies a subgroup of periodontitis patients with high degree of periodontal inflammation and advanced alveolar bone loss, but we do not find support for a link between periodontitis or anti-Rgp IgG and ACPA status in PerioGene North. Given the association between anti-Rgp and alveolar bone loss, the mechanistic role of gingipains in bone resorption should be experimentally explored.