We have previously shown that inflammasome-associated caspase-1 is activated in human macrophages in response to influenza A virus infection resulting in the secretion of proinflammatory cytokines [4, 5] . Subsequently, it has been shown that the inflammasome structure that activates caspase-1 during influenza A virus infection is NLRP3 [10] [11] [12] 41, 42] . Our present results show that influenza A virus infection of human macrophages is associated with endolysosomal leakage of cathepsins to the cytosol. This was followed by the activation of inflammasomeassociated caspase-1 and secretion of IL-18, caspase-1, and mature forms of cathepsins. Furthermore, cathepsin specific inhibitor Ca-074-Me completely inhibited secretion of IL-18 and caspase-1 demonstrating that inflammasome activation during influenza A virus infection is completely dependent on cathepsin activity. These results indicate that lysosomal proteases, cathepsins, are an essential part of pro-inflammatory innate immune response during viral infections.