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Macrophage activation and invasion by Porphyromonas gingivalis is modulated by PPAD and accessory fimbriae subunits

ABSTRACT: Background: Porphyromonas gingivalis is a master manipulator of host immune responses in periodontium. Peptidyl arginine deiminase (PPAD), a recently described virulence factor of P. gingivalis, responsible for both host- and bacterium-derived proteins and peptides citrullination, also plays an important role in hijacking immune responses. While PPAD’s modification of fimbrial subunits (FimCDE) affects TLR2 signaling in fibroblasts, its impact on immune cells remains unclear. Methods: Human monocyte-derived macrophages (MDMs) were stimulated with wild-type or mutant P. gingivalis strains and isolated fimbriae. Inflammatory responses were assessed by measuring cytokine expression and secretion, transcriptional changes using RNA-seq and Pi3K/Akt pathway activation, while bacterial invasion through flow cytometry, fluorescent microscopy and intracellular survival assay. Results: PPAD-modified fimbriae enhanced MDM proinflammatory responses, such as PGE2- related gene expression as well as cytokines secretion, while fimbriae from accessory subunit mutants failed to induce inflammation. PPAD modification of accessory fimbrial subunits was found to protect P. gingivalis from killing by macrophages. PPAD and accessory fimbriae subunits were involved in complex immune evasion strategies, upregulating genes associated with viral infections or interactions with T cells. Conclusions: These findings highlight the importance of protein citrullination in TLR2-dependent signaling and provide insight on how P. gingivalis subverts host immune responses.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304218 | GEO | 2026/03/11

REPOSITORIES: GEO

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Project description:Periodontitis affects 47.1% of adult population in the U.S. Porphyromonas gingivalis is an opportunistic oral pathogen that colonizes the oral mucosa, invades myeloid dendritic cells and accesses the bloodstream, brain, placenta and other organs in human with periodontitis. Periodontitis also sustains a chronic long-term pro-inflammatory immune disorder, potentially contributing to other systemic conditions such as cardiovascular disease, type 2 diabetes mellitus, adverse pregnancy outcomes, and osteoporosis. However, the role of P. gingivalis minor and major fimbriae in DC-SIGN-TLR2 crosstalk during traverses from oral mucosa to these distant sites and its influence on survival of P. gingivalis within DCs and its immune-mechanism involve at molecular/transcriptome level has not been examined. In this study to address the role of fimbriae we utilized defined bacterial mutants that solely express minor fimbriae (Mfa1+Pg), major fimbriae (FimA+Pg) or are deficient in both fimbriae (MFB) and compared with un-infected control. P. gingivalis strains were maintained anaerobically (10% H2, 10% CO2, and 80% N2) in a Forma Scientific anaerobic system glove box model 1025/1029 at 37Â°C in Difco anaerobe broth MIC. Mutant strains were maintained using erythromycin (5 Î¼g/ml) for mutant Mfa1+Pg, tetracycline (2 Î¼g/ml) for mutant FimA+Pg and both erythromycin and tetracycline for double fimbriae mutant MFB. Bacterial suspensions were washed five times in PBS and re-suspended for spectrophotometer reading at OD 660 nm of 0.11, which previously determined to be equal to 5 x 107 CFU. For bacterial CFSE staining, the suspension were washed (3 times) and re-suspended in 5 Î¼M of CFSE in PBS. The bacteria were incubated for 30 min at 37Â°C in the dark. MoDCs were pulsed with Pg381, Mfa1+Pg, FimA+Pg and MFB at 10 MOI and incubated with the MoDCs for 12 hours and each experimental condition was performed in triplicate. To facilitate our understanding on host immunity and defense mechanism of this pathogen, here we used the Illumina High-throughput RNA-seq transcriptome profiling to investigate the myeloid dendritic cells response to oral Amphibiont (1. Pg381, 2. Mfa1+Pg, 3. FimA+Pg, 4. MFB and 5. Un-infected control group).

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Macrophage activation and invasion by Porphyromonas gingivalis is modulated by PPAD and accessory fimbriae subunits

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