Periodontitis Primes the Oral Microenvironment for PS-Dependent Non-Canonical Entry Pathways Linked to 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, may heighten susceptibility to SARS-CoV-2 through inflammation-driven upregulation of non-canonical viral entry pathways. In this study, we investigated genes in the phosphatidylserine (PS)-dependent pathway, including ADAM17, ATP11c, TIM1, TIM3, and TIM4, in gingival tissue, saliva, and oral keratinocytes to define how PD and SARS-CoV-2 coordinately modulate oral viral entry mechanisms. Prepandemic gingival biopsies revealed significant upregulation of all non-canonical receptors in inflamed tissue, indicating that PD alone establishes a permissive molecular environment for PS-mediated microbial entry. 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 synergistic effects of viral exposure and periodontal inflammation. In vitro co-infection of primary human oral keratinocytes with SARS-CoV-2 and periodontal pathogens (P. gingivalis, A. actinomycetemcomitans) induced robust, synergistic activation of PS-dependent entry genes, particularly TIM family receptors. Together, these findings identify PS and its associated receptors as inflammation-responsive mediators that expand SARS-CoV-2 entry routes in the oral mucosa. This work highlights a mechanistic intersection between COVID-19 and periodontal disease, with implications for viral persistence, immune dysregulation, and long-term oral health outcomes.