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Periodontitis Primes the Oral Microenvironment for PS-Dependent Non-Canonical Entry Pathways Linked to SARS-CoV-2
Araceli Valverde1, Kristelle Capistrano1, Raza Ali Naqvi1
1Department of Periodontics, University of Illinois Chicago, Chicago, Illinois, USA, 60612.
Research Square
|April 27, 2026
Summary
Periodontal disease (PD) creates oral conditions permissive to SARS-CoV-2 entry. Combined with COVID-19 infection, this synergistically increases viral entry pathways via phosphatidylserine (PS)-dependent mechanisms.
Area of Science:
- Oral biology
- Infectious diseases
- Immunology
Background:
- SARS-CoV-2 infects beyond the respiratory tract, with the oral cavity being a key site.
- Periodontal disease (PD), a chronic inflammatory condition, may increase susceptibility to SARS-CoV-2.
- Non-canonical viral entry pathways, particularly those dependent on phosphatidylserine (PS), are implicated.
Purpose of the Study:
- To investigate the role of PS-dependent genes (ADAM17, ATP11c, TIM1, TIM3, TIM4) in oral tissues during PD and SARS-CoV-2 infection.
- To define how PD and SARS-CoV-2 infection coordinately modulate oral viral entry mechanisms.
- To explore the intersection of periodontal inflammation and viral activity in the oral cavity.
Main Methods:
- Analysis of gingival biopsies, saliva, and oral keratinocytes for PS-dependent pathway genes.
- Comparison of gene expression in prepandemic and post-vaccination cohorts with and without PD.
- In vitro co-infection models using SARS-CoV-2 and periodontal pathogens (P. gingivalis, A. actinomycetemcomitans).
Main Results:
- Pre-existing PD upregulated non-canonical receptors in inflamed gingival tissue, creating a permissive environment for PS-mediated entry.
- COVID-19 positive individuals with PD showed elevated salivary receptor expression and PS levels, indicating synergistic effects.
- In vitro co-infection induced synergistic activation of PS-dependent entry genes, especially TIM receptors.
Conclusions:
- Phosphatidylserine (PS) and its receptors are inflammation-responsive mediators that enhance SARS-CoV-2 entry into oral mucosa.
- A mechanistic link exists between COVID-19 and periodontal disease, impacting viral persistence and oral health.
- Findings have implications for understanding viral immune dysregulation and long-term oral health outcomes.
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