Salivary microRNA Profiling of Long COVID Subjects Reveals Host-Encoded Regulators of Inflammation and Viral Persistence

Periodontal disease (PD) and SARS-CoV-2 infection converge upon shared immunoinflammatory axes, yet the molecular mechanisms underpinning their interplay remain insufficiently characterized. Herein, we delineate a comprehensive salivary microRNA (miRNA) repertoire from convalescent individuals with prior SARS-CoV-2 infection sampled 3-6 months post-diagnosis who fulfilled criteria for post-acute sequelae of COVID-19, yielding novel insights into the post-viral oral milieu. Salivary miRNA sequencing showed broad suppression of miRNAs in PD, consistent with sustained immune dysregulation. Compared with COVID-19-/PD- controls, COVID-19+/PD+ individuals displayed 32 differentially expressed miRNAs, all downregulated and this pattern was independently validated in a post-vaccination cohort for selected candidates. Pathway analysis linked these miRNAs to core inflammatory signaling modules, including Ras, MAPK and NF-kB, converging on IL-1B and TNF-centered networks implicated in both PD and COVID-19. Overexpression of miR-30e-3p, miR-106-3p and miR-652-3p suppressed NF-kB activation and pro-inflammatory cytokine production in TLR-stimulated oral keratinocytes, whereas their inhibition enhanced inflammatory activity. These miRNAs also directly targeted SARS-CoV-2 spike and nucleocapsid transcripts and reduced viral RNA and antigen abundance in infected epithelial cells. Together, these findings identify salivary miRNAs as endogenous regulators of oral inflammatory tone and antiviral defense and establish a mechanistic link between periodontal inflammation and post-COVID oral pathology.