Previous findings reported that H1N1 influenza A infection was characterized by a T-helper cell response, in particular type 1 and type 17 T-helper cells [28]. Conversely, a lack of T-helper cell response was noted in the bacterial pneumonia gene signature, which was characterized by large representation of neutrophil-expressed genes. This finding reinforces our finding that our 29-gene viral signature reflects the actual immune response of the host during influenza infection.Our study also revealed two surprising new findings. First, immune and inflammatory pathways genes have been traditionally thought of as the main determinants of host response to influenza infection. Our findings show that genes linked to the cell cycle and its regulation were the main determinants of the host response in influenza infection, whereas most immune and inflammatory genes were downregulated. This downregulation points more toward a state of immune suppression, particularly so for many interleukin-receptor and signaling pathways. This finding has potential diagnostic implications. For decades, inflammatory or immune response genes and proteins have been investigated for their utility as diagnostic markers for bacterial and viral infection. However, many of these markers have failed because of the lack of specificity (for example, the marker is expressed in both viral and bacterial infection). Our results suggest that cell cycle-related genes may provide alternative candidates as diagnostic markers.The second surprising finding is that our study failed to identify an immune response specific to bacterial pneumonia. A small number of genes were dysregulated uniquely in the bacterial infection group. However, analysis of these genes revealed that no particular biological pathways or networks were significantly overrepresented. The gene-expression pattern of the bacterial group was most similar to the SIRS cohort, as demonstrated by the large overlap of genes between these two groups in the Venn diagrams (Figure (Figure1)1) and in the cluster analysis (Figure (Figure7).7). Further evidence supporting a lack of a unique immune response to bacterial pneumonia was mounted when the SIRS and bacterial pneumonia cohorts were compared directly, by using the linear mixed model. No genes were significantly differently expressed between these two phenotypes at 5% FDR (data not shown). The lack of a bacteria-specific gene signature contrasts sharply with the discovery of the 29-gene virus-specific signature.In this study, we focused on one specific cause of viral pneumonia, pandemic H1N1 influenza A.