ABSTRACT This proposal addresses the nature of interferon (IFN)-based antiviral responses at the oral mucosal barrier, and the bacterial factors that impact their efficacy. IFNs are antiviral cytokines that are critical in limiting all aspects of viral infection. We found that Type III IFNs or IFN lambdas (IFN-λs) are preferentially expressed by oral epithelial cells, and IFN-λ-associated signaling confers robust, broad-spectrum, antiviral immunity at the oral mucosal barrier. Bacterial colonizers at barrier sites have the potential to modulate host susceptibility to viral infection. Consistent with this, we found that Porphyromonas gingivalis (Pg), which is associated with oral dysbiosis and periodontal disease, singularly and totally dampened all aspects of IFN signaling in response to viral agonists. The overall goal of this study is to characterize the effect of Pg-induced IFN-λ suppression on viral clearance and neutrophil function, as well as determine the relevance of IFN-λ suppression for Pg colonization. Our main hypothesis is that IFN-λ is preferentially induced at the oral mucosal barrier and confers antiviral immune protection without inducing inflammation. Further, we hypothesize that Pg disengages both homeostatic and inducible IFN-λ responses, thereby enhancing host susceptibility to oral viral infection and to chronic inflammation, as well as contributing to Pg persistence. These hypotheses will be tested in the following specific aims. Aim 1: Characterize the impact of Pg-mediated suppression of IFN-λ signaling on viral clearance in vivo. Aim 2: Determine the contribution of IFN-λ mediated regulation of neutrophil effector functions to tissue damage and persistent inflammation during oral viral infections. Aim3: Determine the role of inactivation of IFN signaling in Pg persistence during infection. This study will provide fundamental novel information on the role of Pg in the suppression of anti-microbial inflammatory responses at the oral mucosal barrier. Additionally, an increased understanding of the factors that provide antiviral resistance in the oral cavity is highly significant as a large number of viruses, including SARS-Cov2, can infect oral tissues and cause local and systemic disease.