Proteinase-Activated Receptor-2 Agonist Activates Anti-Influenza Mechanisms and Modulates IFNγ-Induced Antiviral Pathways in Human Neutrophils

Proteinase-activated receptor-2 (PAR(2)) is expressed by human leukocytes and participates in the development of inflammatory diseases. Recent studies demonstrated an ability of PAR(2) agonist to enhance IFNγ-induced antiviral responses of human leukocytes. However, the precise cellular antiviral defense mechanisms triggered in leukocytes after stimulation with IFNγ and/or PAR(2) agonist remain elusive. Therefore, we aimed to identify neutrophil defense mechanisms involved in antiviral resistance. Here we demonstrated that PAR(2) agonist enhanced IFNγ-related reduction of influenza A virus (IAV) replication in human neutrophils. PAR(2)-mediated decrease in IAV replication was associated with reduced NS-1 transcription. Moreover, PAR(2)-dependent neutrophil activation resulted in enhanced myeloperoxidase degranulation and extracellular myeloperoxidase disrupted IAV. The production of ROS was elevated in response to PAR(2) activation. Interestingly, IFNγ did not influence both effects: PAR(2) agonist-triggered myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which are known to limit IAV infections. In contrast, orthomyxovirus resistance gene A (MxA) protein expression was synergistically elevated through PAR(2) agonist and IFNγ in neutrophils. Altogether, these findings emphasize two PAR(2)-controlled antiviral mechanisms that are independent of or modulated by IFNγ.