<i>Porphyromonas gingivalis</i> Suppresses Interferon‐Gamma Signaling in Macrophages Through a Contact‐Dependent, Gingipain‐Mediated Mechanism

Interferon signaling serves as a crucial defense mechanism for host cells against intracellular pathogens. Interferon-gamma (IFN-γ) binding to macrophages impacts the expression of approximately 2000 genes, activating them to enhance intracellular bactericidal activity. While various immune evasion strategies of Porphyromonas gingivalis have been extensively studied, the specific mechanisms by which it suppresses IFN-γ-mediated macrophage activation remain insufficiently characterized. In this study, we elucidated the molecular mechanism by which P. gingivalis suppresses interferon signaling in macrophages, with a particular focus on STAT1 transcript abundance, because STAT1 encodes a central transcription factor in the IFN-γ pathway. RNA-seq analysis revealed that P. gingivalis infection reduced the mRNA abundance of approximately 41% of genes upregulated following IFN-γ stimulation, including STAT1 transcripts and other interferon-related genes. Further experiments showed that direct contact between the bacterium and host cells is necessary for this inhibition. This process involves the Type IX Secretion System (T9SS) and gingipains. Notably, strains lacking all gingipains (Kgp, RgpA, and RgpB) failed to suppress STAT1 transcript abundance and instead allowed nuclear translocation of phosphorylated STAT1. These gingipain-deficient strains also exhibited reduced invasive ability, correlating with their diminished capacity to suppress interferon signaling and macrophage activation. In conclusion, our findings demonstrate that P. gingivalis inhibits interferon signaling in macrophages through intracellular infiltration, with T9SS and gingipains playing essential roles in this immunosuppressive mechanism. These results provide valuable insights into the immune evasion strategies of P. gingivalis and suggest potential therapeutic targets for combating periodontopathic diseases.