In mice infected with the influenza virus, an increased activation of the p53 dependent DNA-damage response is associated with reduced lung inflammation and better survival. Put together, our findings reveal a systematic loss of control by the host leukocytes over key cellular functions, including DNA synthesis, mitotic exit and self-repair response. As infection resolved, these perturbations subsided and were accompanied by a recovery in host response including lymphocyte, monocyte and neutrophil cell counts. Leukocyte proliferation is an important of part of the host immune response and is critical for the clearance of influenza infection. Cell cycle perturbations may impair leukocyte proliferation, leading to a significantly diminished host response and consequently a more severe infection. Our results therefore suggest a plausible mechanism for explaining why some individuals succumb to severe influenza infection whilst others recover quickly after having only a relatively mild illness. Previous studies have focused predominantly on the role of immune cells in lung parenchyma and local lymphoid tissue in driving disease progression. It is commonly believed that disease progression occurs when influenza virus replication overwhelms the local defence mediated by immune cells in the lung. However, such a model fails to explain why viral loads assayed from airway samples in infected human are similar regardless of disease severity, a finding consistently observed in the recent pandemic H1N1 influenza infection. This study provides an alternative mechanism to explain disease progression CT99021 during influenza infection. Our findings suggest that, during primary influenza infection, an unabated cell cycle dysregulation in systemic immune cells diminishes host response. Host cells respond by programmed cell death to eliminate non-viable cells and to limit genome damage. The manner by which the influenza virus modulates this response may very well represent the distinguishing features between a mild, self-limiting illness and a highly lethal infection. There are limitations in our study. First, different influenza virus strains were used in the study. Ideally, each group being infected with the same virus will allow a more valid comparison between the groups. Second, an inherent limitation with observational study is that groups differ not just in the phenotype of interest, but also in other characteristics as well. These other characteristics could have confounded our findings. Third, two different microarray platforms were used in generating data for this study. The difference in technology may have introduced artifectual differences that may potentially dilute the real biological signals. In conclusion, our study extends the established influenza model to include a key role for circulating leukocyte response to infection. The discovery of a significant pathology in circulating leukocytes provides an additional perspective from which to interrogate the role of host response in influenza infection.