Viruses are among the most frequent causes of acute and chronic illness. Despite the scope of this problem, the accuracy of diagnosis and efficacy of treatment for most viral infections is limited in effectiveness. To address this issue, we have developed an alternative strategy that is aimed at defining and improving on the antiviral host response. We focus particularly on respiratory infection using a system of primary-culture and infection of human airway epithelial cells. We propose that improving Stat1 function in airway epithelial cells will enhance antiviral defense. Accordingly, we have engineered a modified Stat1 with strategic double-cysteine mutations (Stat1-CC) that is hyperresponsive to endogenous levels of IFN. Expression of Stat1-CC markedly decreases the level of viral replication both in vitro and in vivo. We are now extending our approach to the study of emergent pathogens.