In this study, we show a novel function of PrPC to induce anti-inflammatory M2 macrophage polarization through activation of Src family kinases (SFKs), and that anti-PrP monoclonal antibodies (mAbs) stimulated the novel activity of PrPC inducing M2 macrophages and thereby protected mice from lethal infection with IAVs. Here, PRNP is linked to infection.