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Filifactor alocis is an emerging oral pathogen, and approximately 50% of known F.alocis strains encode and express a Repeats-in-Toxin (RTX) protein, FtxA. FtxAappears to be associated with both progress and severity of periodontal disease.Mechanisms are not yet known but could be linked to increased loads of F. alocisin ftxA-positive strains. Here, we investigated mechanistic correlations based onFtxA-activity, as present in F. alocis cells and extracellular vesicles and as arecombinant protein, exploiting THP-1 macrophage-like cells. For this, we usedthe ftxA-expressing strain, ATCC 35896 (ftxA+), and F. alocis 148B-17U (ftxA−),which naturally lacks the ftxA gene. Using RNA sequencing analysis (RNA-Seq) andcytokine array analysis, we have pinpointed a role of FtxA in shifting host responsetoward immunosuppression, also inhibiting apoptosis and immune cellrecruitment, and with a potential role in downregulating mitochondrial andoxidative phosphorylation pathways. Such role(s) could provide a plausibleexplanation why FtxA is associated with progress and severity of periodontaldisease, and further studies on FtxA-host cell interactions might reveal novelpotential therapeutic targets.