We next used a mouse infection model to assess the contribution of the 1918 HA and NA genes to viral pathogenesis [32] . These studies, led by John Kash, evaluated mouse-adapted A/WSN/ 33 viruses that were engineered to contain the HA and NA genes from the 1918 virus or from the nonlethal A/New Caledonia/20/99 virus. Microarray analyses performed on lung tissues isolated from all infected animals showed the activation of many genes involved in the inflammatory response, including cytokine, apoptosis, and lymphocyte genes. However, consistent with histopathology analysis, the parental and 1918 HA/NA:WSN recombinant viruses showed increased expression of genes associated with activated T cells and macrophages, as well as genes involved in apoptosis, tissue injury, and oxidative damage that were not observed in mice infected with the New Caledonia HA/NA:WSN virus. These studies documented clear differences in gene expression profiles that were correlated with pulmonary disease pathology and suggested that an intrinsic property of the 1918 HA and NA proteins may be the production of a longer and more severe immune response culminating in a more destructive viral infection.