We developed human (HeLa) cell lines in which mouse hepatitis virus receptor (MHVR) levels could be regulated by addition of tetracycline. We used these cell lines to determine whether MHVR levels impact the degree of cytopathology induced by infection with the lytic MHV A59 strain. Two cultures were studied; HeLa-MHVRlo (less than 3,000 molecules per cell) and HeLa-MHVRhi (300,000 molecules per cell). Both supported synthesis of infective A59 virus. However, the MHVRlo cells showed no virus-induced cytopathology while the MHVRhi cells uniformly died within 14 hours after infection. This cell death was not related to virus-induced syncytium formation as it occurred even in subconfluent cells overlaid with fusion-blocking antiviral antibodies. MHV A59 spike proteins produced by vaccinia vectors also killed the MHVRhi cells within 12 hours postinfection--MHVRlo cells infected in parallel were intact as judged by trypan blue exclusion. Our current hypothesis is that the accumulation of intracellular complexes composed of spike and MHVR proteins leads to acute single cell lysis.