Periodontitis is a chronic inflammatory disease affecting the tissues supporting the teeth. Porphyromonas gingivalis and Tannerella forsythia are important pathobionts in periodontitis shown to modulate host immune system. We tested the hypothesis that inhibition of the sialidases of these organisms might modulate cytokine production of epithelial cells with which these bacteria interact during infection. Chemoenzymatically synthesized di-fluoro sialic acid analog 2e3aDFNeu5Ac9N3 known to have inhibitory activities against other bacterial sialidases and the recombinant human cytosolic sialidase hNeu2 (Li et al., 2019) was used. Inhibition studies using whole cells and the sialidases of T. forsythia and P. gingivalis showed 2e3aDFNeu5Ac9N3 to have potent activity. Using purified NanH it was established that it’s mechanism of action was as a competitive inhibitor. Furthermore, it was not toxic to oral epithelial cells at the concentrations at which it inhibits these enzymes (1µM) and at which it inhibits invasion of these cells by TF and PG (1 and 4µM). Additionally, innate immune responses of H357 oral epithelial cells in the presence/absence of 2e3aDFNeu5Ac9N3 and TF(ATCC43037)/PG(0381) or using a strain lacking sialidase were assessed using flow cytometry. This revealed that sialidase activity appears to modulate levels of several pro-inflammatory cytokines; namely interleukin-6 (IL-6), IL-8 and IL-1β in the cell supernatants. Summarily, the sialidase of T. forsythia upregulated cytokine secretion in H357 cells which was abrogated significantly by 2e3aDFNeu5Ac9N3 with minimal cytotoxic effects on the oral epithelial cells. This compound may have potential for future development. Keywords: Sialidases, T.forsythia, P.gingivalis, Cytokines, 2e3aDFNeu5Ac9N3