Periodontal disease is a chronic multifactorial disease triggered by a complex of bacterial species. These interact with host tissues to cause the release of a broad array of pro-inflammatory cytokines, chemokines, and tissue remodelers, such as matrix metalloproteinases (MMPs), which lead to the destruction of periodontal tissues. Patients with severe forms of periodontitis are left with a persistent pro-inflammatory transcriptional profile throughout the periodontium, even after clinical intervention, leading to the destruction of teeth-supporting tissues. The oral spirochete, , is consistently found at significantly elevated levels at sites with advanced periodontal disease. Of all virulence factors that have been described, its chymotrypsin-like protease complex, also called dentilisin, has demonstrated a multitude of cytopathic effects consistent with periodontal disease pathogenesis, including alterations in cellular adhesion activity, degradation of various endogenous extracellular matrix-substrates, degradation of host chemokines and cytokines, and ectopic activation of host MMPs. Thus, the following model of -human periodontal ligament cell interactions may provide new knowledge about the mechanisms that drive the chronicity of periodontal disease at the protein, transcriptional, and epigenetic levels, which could afford new putative therapeutic targets. PLOS Pathog (2021), DOI: 10.1371/journal.ppat.1009311.