Periodontitis modulates PS-dependent non-canonical entry pathways associated with SARS-CoV-2 susceptibility

SARS-CoV-2 infection extends beyond the respiratory tract, with the oral cavity emerging as a critical site of viral activity shaped by epithelial receptor expression, microbial interactions, and inflammatory status. Periodontal disease (PD), a chronic dysbiotic condition, co-occurs with alterations linked to SARS-CoV-2 susceptibility markers through inflammation-driven upregulation of non-canonical viral entry pathways. In this study, we aimed to determine whether periodontitis-associated inflammatory changes are accompanied by activation of the PS/TIM pathway and whether this pathway correlates with molecular patterns that SARS-CoV-2 can potentially engage for cellular entry. Expression of phosphatidylserine (PS)–dependent pathway genes, including ADAM17, ATP11c, TIM1, TIM3, and TIM4, was examined in gingival tissue, saliva, and oral keratinocytes. Prepandemic gingival biopsies revealed significant upregulation of all non-canonical receptors in inflamed tissue, indicating that PD alone establishes a molecular environment associated with PS-mediated microbial entry markers. In a post-vaccination cohort, salivary expression of these receptors was markedly elevated in COVID-19–positive individuals with PD, accompanied by significantly increased salivary PS levels, suggesting co-occurring patterns of viral exposure and periodontal inflammation. In vitro combined exposure of primary human oral keratinocytes with SARS-CoV-2 and periodontal pathogens ( P. gingivalis , A. actinomycetemcomitans ) induced robust, concordant activation of PS-dependent entry genes, particularly TIM family receptors. Collectively, these findings link periodontitis-associated inflammation with enhanced PS/TIM pathway activity and suggest that this inflammatory environment co-occurs with molecular conditions related to SARS-CoV-2 infection pathways in the oral mucosa. This study highlights an association between COVID-19 and periodontal disease, with implications for viral activity, immune dysregulation, and long-term oral health outcomes.