Apoptosis is an innate immune response by which infected and other harmful cells are eliminated from the inflamed tissue. In this way intracellular danger signals are not released to extracellular space and inflammation is not further enhanced. We have previously shown that influenza A virus infection of human macrophages is associated with activation of caspase-3 [5, 23] which is the hallmark of apoptosis. Lysosomal proteases cathepsins are known to act in concert with caspases in apoptotic cell death [46] . Our current data shows that influenza A virus infection of human macrophages is associated with rapid cytoplasmic upregulation of cathepsins indicating lysosomal rupture upon infection. Furthermore, we show that cathepsins act upstream of caspase-3 and that their activity is essential for progression of apoptosis.