Respiratory viruses cause considerable morbidity and mortality worldwide and represent a major threat to the overall global health. In particular, aged populations experience increased disease burdens, especially from viruses that emerge suddenly from animal reservoirs. In fact, some of the most serious respiratory viruses are animal viruses, like influenza viruses and severe acute respiratory coronaviruses, which have jumped the species barrier, adapted to the human host and caused severe end stage lung disease resulting in death. It is interesting to note that these viruses generally produce a range of diseases varying from mild common colds to devastating acute lung failure. What causes this variable disease in the human host? Well, it is well recognized that the human genome contains large numbers of sequence changes that are unique to each individual and that these changes, called susceptibility loci, influence disease severity following virus infection. Surprisingly, the identity and function of these genes are not unknown, nor is it understood how aging influences this process. Consequently, the goal of our proposal is to develop and use novel young and aged model systems to identify the genes and their functions that differentially regulate the severity of respiratory disease outcomes following virus infections as a function of aging, using the SARS-CoV and influenza as model systems. Moreover, we will test the idea that a detailed understanding of this process will allow researchers/physicians the ability to accurately predict disease outcomes prior to infection. In each individual, this information will allow us to design an effective treatment strategy, beforehand, that will best increase the chance of survival at the individual level while simultaneously developing new approaches and broad based drugs that target many important respiratory viruses, rather than a single type.