Influenza Virus-Containing Immune Complexes Activate Platelets Through FcγRIIa Resulting In Bioactive Lipid Synthesis and Microparticle Release

After red blood cells, platelets represent the most abundant cell lineage in blood, where they sentinel the vasculature and play crucial functions in haemostasis and the prevention of bleedings. Platelets also express a vast array of immune mediators and receptors, suggesting that they can also be regarded as tiny immune cells capable of the recognition of pathogens. Indeed, platelets express functional Toll-like receptors and are thought to actively participate to innate immunity. During severe cases of H₁N₁ influenza A virus infection, circulating platelets display markers of activation. The specific platelet activation triggers during Influenza infection remain however unknown. In this study, we incubated human platelets with H₁N₁ influenza A virus (IAV) and monitored platelet activation. We found that IAV is a highly potent inducer of de novo lipid mediators production and a trigger for the release of microparticles from platelets. This activation process takes place independently of the Toll-like receptor 4 and requires the presence of serum, pointing to the contribution of soluble factor(s) present in blood. We observed that the virus scaffolds with immunoglobulin G to form large immune-complexes (∼1micron in size) that activate platelets through the engagement of FcgRIIA. Accordingly, the serum of naïve mice housed in a pathogen-free facility is ineffective at initiating human platelet activation when incubated in the presence of IAV. Intrigued by the fact that all the tested human sera were capable of forming immune complexes with IAV, we hypothesized that significant antibody cross-reactivity between different influenza viruses was sufficient to promote the formation of virus-containing immune complexes. Using in vivo approaches, we found that the antibodies from H₃N₂ influenza virus-immunized mice generate immune complexes when put in presence of H₁N₁, activating human platelets and transgenic mouse platelets that express FcgRIIA. Taken together, our observations demonstrate that beyond their activities in haemostasis and innate immunity, platelets can also play a role during the active stage of adaptive immune responses against pathogens through FcγRIIa activation.