Development of a murine hypothermia model for study of respiratory tract influenza virus infection.

A hypothermia model was developed to predict mortality and morbidity caused by respiratory influenza virus infection in mice. To increase virulence, egg-propagated influenza A/PR/8 virus was adapted for growth in mice by four blind serial passages. The mouse-adapted influenza A virus was then used to infect groups of BALB/c mice via the intranasal route, and the 50% lethal dose (LD50) was determined. Rectal temperature of the infected mice was monitored daily, and survival rate was determined at day 14 after infection. The lowest average body temperature recorded in infected mice was approximately 10 degrees C below that in noninfected mice. In mice that developed hypothermia, with body temperature of 32 degrees C or lower, morbidity and mortality inevitably occurred. In this study, the LD50 and the 50% hypothermia-inducing dose (HID50) for mouse-adapted influenza A virus were compared and calculated to be at the same dose. These results suggest that the HID50 model could be used to predict mortality and morbidity associated with influenza virus infection in mice. This model could potentially be used to substantially reduce the time and extent of suffering inflicted on experimental animals due to viral infections, and therefore may serve as a more humane alternative to LD50 determinations.