Abstract Coronavirus disease 2019 (Covid-19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infecting non-vaccinated and vaccinated people. Covid-19 clinically affects multiple organs including oral mucosa where SARS-CoV-2 replication occurs to deposit virion into saliva in sufficient copies (>1000) to be detected. Public health data reveals Covid-19 and periodontitis disproportionally affects Non-Hispanic Blacks (NHB) and Hispanics (H). We hypothesize that periodontal disease (PD) pre- conditions oral mucosa for persistent oral pathology and oral Post-Acute Sequelae of Covid-19 (PASC). However, the cellular and molecular mechanisms underlying this relationship between Covid-19 and poor oral health outcomes are unclear. Extending our preliminary dataset of oral examination, and immune assessment of Black and Hispanic cohort, our Aim 1 involves a comparative analysis of the impact of vaccination on oral PASC indicators and perturbation in oral immune surveillance. We assessed this relationship before vaccination was available, which provides an opportunity to compare how periodontal health, Covid-19 infection, and the vaccination status affects minority population (NHB/H) versus Non-Hispanic White (NHW) with similar variables and risk for oral PASC. Saliva and gingival crevicular fluid (GCF) will be examined to perform comprehensive profiling of immune cells (both myeloid and lymphoid compartments) and assess mediators of immune cell activation, polarization and exhaustion contributing to impaired oral immunity. We will decipher three important gaps of knowledge in an underserved cohort: (1) whether infectivity of SARS-CoV-2 is affected by poor oral health?, (2) does Covid-19-induced inflammation worsen pre-existing periodontal health, and (3) does Covid-19 vaccination lessen oral PASC viz. periodontal inflammation? In Aim 2, we will examine whether previous intracellular periopathogens enhance risk for continual reinfection of SARS-CoV-2 and promote oral PASC. Our lab has optimized an in vitro infection model of SARS-CoV-2 in primary gingival epithelial cells (GEC) to dissect the role of periodontal pathogens (both bacteria and herpesviruses) enhancing viral tropism and replication. Characterizing periodontal microbe-SARS-CoV-2 interaction will unravel novel mechanisms that can be targeted to mitigate oral PASC. Our findings will support that periodontal pathogens increase host susceptibility to SARS- CoV-2 infection by providing a conducive microenvironment for viral tropism, and persistence. Next, we will decipher SARS-CoV-2-mediated mechanisms of impairing periodontal immunity. To this end, we will characterize the novel role of SARS-CoV-2- open reading frames (ORFs) in modulating oral antiviral and antibacterial immunity by examining viral entry and replication, expression of Pathogen Recognition Receptor (PRR) and downstream signaling activation. Successful outcomes of this study will disclose no...