PB0400 - The Janus-face of platelet PAR4: dose-dependent host protective and detrimental roles in influenza A virus infection of mice.

Background: Severe IAV infection is characterized by excessive lung inflammation and pathology. Protease-activated receptor 4 (PAR4) is expressed by megakaryocytes/platelets, immune cells, and lung epithelial cells. PAR4 is the only functional thrombin receptor on murine platelets. We found that a global PAR4 deficiency in mice was associated with increased IAV-induced pathology and mortality in a low dose IAV infection model. Moreover, we showed that PAR4 inhibition in wild-type mice worsened the pathology in a low dose IAV model but was protective in a high dose IAV model.

Aims: To investigate the role of platelet PAR4 in low and high dose IAV infection in mice.

Methods: Mice with PAR4 deficiency on megakaryocytes/platelets (PAR4fl/fl;PF4Cre+, PAR4ΔPlt) and controls (PAR4fl/fl) were infected with mouse-adapted IAV at low and high doses. Airway inflammation, lung virus genome levels, IFN responses and global Lung function were analyzed. In addition, mice were subjected to poly IC (100 µg intranasally) daily for 3 days to induce dsRNA lung dysfunction.

Results: Control and PAR4ΔPlt mice had comparable expression of inflammatory mediators and cellular inflammation in BALF before IAV infection in both IAV models. However, PAR4ΔPlt mice exhibited increased IFN responses resulting in reduced IAV genomes in the lung 3 dpi compared to control mice in both IAV models. Interestingly, lung injury markers, including the calculated enhanced pause (PenH, airway resistance), were significant higher in PAR4ΔPlt compared to control mice 7 dpi in the low dose IAV model but the reverse was observed in the high dose. Moreover, in virus-like stimulation with poly IC, PAR4ΔPlt mice exhibited more lung injury and more severe lung dysfunction compared to control mice.

Conclusion(s): We found that platelet PAR4 is protective in a low dose IAV infection mouse model but contributes to pathology in a high dose IAV infection mouse model.