The highest incidence of influenza infection occurs in children in the age group of 5-9 years. The very young and the very old suffer the highest mortality rate from infection with influenza virus. Continues susceptibility to reinfection with influenza virus occurs throughout life and most serious influenza infections are reinfections, rather than primary infections. In order to minimize or prevent influenza-mediated lung inflammation, it is critical to understand the characteristics of the cellular response to both primary and recurrent influenza infection. Although many aspects of the cellular and humoral response to influenza virus infection have been characterized in the murine model, significant gaps remain in our knowledge. Specifically, little is known about the role that chemokines play during infection. This project is designed to determine the effects of beta-chemokines on pulmonary epithelium and T cell function during a primary and secondary influenza virus infection. Our preliminary data have demonstrated that, in vivo, the beta- chemokine, macrophage inflammatory protein 1 alpha (MIP-1alpha), is an important contributor to the pulmonary infiltration post influenza infection. Knockout mice with the MIP-1alpha gene inactivated by homologous recombination have markedly attenuated pulmonary cellular infiltrate post influenza virus infection when compared with wildtype mice which express MIP-1alpha. The specific aims of this project are 1) to develop two additional beta-chemokine knockout strains of mice: one with an inactivated RANTES gene and the other with an inactivated MIP- 1beta gene; 2) characterized expression of the beta chemokines during primary and secondary influenza A virus infection in the knockout and wildtype mice; 3) to define the role of beta chemokines in recruitment of CD4+ and CD8+ T cells to the lung during primary and recurrent influenza infection using knockout and wildtype mice and 4) to define the role to beta chemokines in T cell activation during influenza virus infection in both knockout and wildtype mice. This project will provide a model for the effect of beta-chemokines on the development of influenza-induced pulmonary inflammation and may provide new directions for the therapeutic interventions.