Influenza and pneumonia together account for more than 36,000 deaths and 114,000 hospitalizations annually in the United States. Despite the availability of an excellent healthcare system and effective antimicrobials directed against both influenza and bacterial causes of pneumonia, a substantial number of these deaths are due to secondary bacterial pneumonia. The molecular mechanisms that underlie the interaction between respiratory viruses and bacteria are largely unknown. Since secondary bacterial infections account for a significant proportion of the deaths that occur during circulation of virulent strains, it is critical that we understand the basis of this synergy before the next highly pathogenic influenza virus enters the population from avian sources or as a result of bioterrorism. This application proposes in vitro and in vivo experiments to study this interaction utilizing an animal model of synergism between influenza virus and Streptococcus pneumoniae developed in the laboratory of the Principal Investigator. The main hypotheses that will be tested are that strain-specific influenza virulence factors cause alterations of innate immunity of the host that allow pneumococcal strains expressing particular proteins to survive and produce disease. A detailed understanding of this interaction will provide information important for surveillance and control of influenza viruses, as well as support for drug and vaccine based interventions aimed at amelioration of human disease and death caused by bacterial superinfection following respiratory viral disease. More broadly, the proposed work addresses an interesting biological question, that of polymicrobial interactions, and should serve as a model and stimulus for investigation of the contribution of multiple organisms to other disease states.