Differential expression of immunoregulatory genes in male and female Norway rats following infection with Seoul virus

Males of many species are more susceptible than females to infections caused by parasites, bacteria, fungi, and viruses. Following inoculation with Seoul virus, male rats have more virus present in target organs and shed virus longer than females. The goal of this study was to test the hypothesis that variation in the expression of genes associated with immune function mediates sex differences in hantavirus infection. Using DNA microarrays, we examined changes in gene expression in lung tissue during the early (when animals are viremic and shedding virus; Day 15 post-inoculation (p.i.)) and late (animals have low levels of infectious virus, but high antibody titers; Day 40 p.i.) phases of infection in adult male and female rats. After normalizing the gene expression levels from infected animals to the gene expression levels from same-sex uninfected controls, our data revealed that 1,813 genes were differentially expressed between the sexes during infection. The expression of key transcriptional factors (e.g., eIF-2alpha, NF-kappaB, IRF-1, NF-IL-6, and STAT6) and genes that encode for proinflammatory (e.g., TNFalphaR, IL-1R, and IL-1RAcP), antiviral (e.g., IFNgammaR and Mx proteins), T cell (e.g., CD3 and TCR), and Ig superfamily (e.g., IgM, IgG, and MHC class I and 11) proteins was higher in females than males. Conversely, males had higher expression of heat shock protein genes (e.g., hsp70) suggesting that cellular stress is elevated in males. These data provide candidate genes and cellular pathways that may underlie sex differences in responses to Seoul virus and possibly other hemorrhagic fever viruses. (C) 2004 Wiley-Liss, Inc.