(549c) Immune Signaling Gene Expression Exhibits Multiple Temporal Patterns in Influenza Infected Mouse Lung

The cytotoxic activities of activated immune cells are known to contribute to the pathogenesis of influenza infections. These immune cells are activated and recruited into the lungs by a myriad of immune signaling molecules produced by influenza infected cells. To gain insights into the temporal expression dynamics of immune signaling molecules during an influenza infection, we used Affymetrix microarrays to measure the expression levels of genes in whole lung extracts of influenza A infected mice (Memphis/71/H3N1). Mouse lungs were harvested at 6, 20, 30, 48, 72, and 96 hours post infection for RNA extraction followed by microarray analysis using Mouse Genome 430 2.0 Genechips. The data were processed using the EDGE time-course statistical analysis package (Storey et al., 2005, PNAS 102(36): 12837-12842). By setting the false discovery rate, i.e. q value, to be statistically significant at 0.00085 we observed that 995 genes had differential time-course expression profiles in flu infected versus control lungs. Interestingly, the immune signaling and signal transduction genes within this group exhibited dramatically different temporal profiles. Some genes, such as: Ccl5, Ccr2, Cxcl12, Cxcl13, Ifnar2, Il13ra1, Il1b, Il2rg, Il6st, Irf1, Mapk9, Nfkb1, Stat1, Tlr2, Tlr3, and Tnfsf13b, were highly up-regulated (>0.65% of maximum value) by 6 hr post infection and remained so over the course of the experiment. Other genes, such as: Ccl2, Ccl7, Cxcl9, Il17r, Il8bp, Il1rn, Oas2, and Stat2, were not up-regulated until 20 hours. Further, genes such as Ccl3, Ccl4, Ifnb, Mx2, and Oas3, were up-regulated only briefly between 20 and 48 hours. These complex temporal profiles suggest that the production of these signaling molecules and the resulting immune cell functions may also fluctuate dynamically in the lungs. These data are being employed in the development of a mechanistic model to describe the pathology of influenza infections.