Put together, these data implicate a major role of circulating leukocytes in influencing disease outcomes in influenza infection. We found that the systemic host response in severe infection differs significantly from that of mild infection. The main differences lay in the cell cycle and apoptosis pathways. Unexpectedly, immune response pathways did not differ significantly between infected groups. Other than TNF and IL-beta, inflammation-related genes that are well established in influenza infection do not discriminate between these groups. Also, interferon response genes do not differ significantly between mild and severe influenza infection. The lack of correlation among established immune/inflammatory markers led us to postulate that disease progression is determined by changes occurring elsewhere, such as in the cell cycle and apoptosis pathways. Further analyses revealed that there is a significantly greater number of cell cycle pathways activated in severe influenza infection compared to mild infection. In addition, the Severe group shows a greater up-regulation of genes encoding for key cell cycle proteins. These cell cycle proteins include cyclin and their associated catalytic kinase enzymes, namely, cyclin E, cyclin A, cyclin B, CDK1 and CDK2. Furthermore, this up-regulation is accompanied by an extensive activation of DNA replication machinery, including the pre-replication complex assembly, MCM complex and Cdt1. The heightened DNA replication activity does not seem to be host cell initiated because cyclin D, the initiator of cell cycle, is paradoxically down-regulated. Importantly, the increased DNA BAY 73-4506 structure synthesis occurs in the context of an abnormally low leukocyte response to infection, indicating that it is not a physiologically normal response. Despite an increase in DNA synthesis, paradoxical changes were seen in the mitotic phase. Here, we found up-regulation of genes opposing the completion of mitosis, including those encoding Securins and the Condensin Complex. Furthermore, there is strong activation of the spindle checkpoint complex, the cellular sensing system that normally prevents premature separation of chromosomes. Together, these proteins maintain chromosome condensation and their up-regulation is known to be associated with delayed mitotic exit. To understand the mechanism underlying this finding, we focused on the anaphase promoting complex, the major regulatory complex that coordinates cell cycle progression and exit from mitosis, which was also the most statistically significant pathway found in our analysis. Here we found abnormal changes in APC and its two co-activators. In subjects with a severe infection, CDC20 is unusually upregulated whilst no activation is seen in hCDH1. Most importantly, the APC gene is not expressed at all. In summary, severe influenza infection is characterized by opposing changes in cell cycle activity and these changes are associated with dysregulated cell cycle control.