Although epithelial cells may not be the main site of viral replication in man in the case of HFRS, viral replication in renal tubular epithelial cells could be the direct cause of renal epithelium dysfunction through direct virus-induced inhibition of signaling pathways necessary for cell viability (ERK1/2), which would be amplified by cytokines elevated in HFRS (TNF-α). This evidence concerns the gene MAPK3 and hemorrhagic fever with renal syndrome.