The genes uniquely upregulated in response to bacterial pneumonia (n = 253) were Tofacitinib Citrate molecular weight not overrepresented in any biological pathway or network ontology, implying a generic inflammatory and immune response, but no specific response to bacterial infection.A larger number of genes were upregulated in SIRS (586 genes). Further analysis showed that they were overrepresented in multiple biological pathway and network ontologies, including inflammatory response (P = 6.3E-6), cell differentiation (P = 1.6E-5), angiogenesis (P = 1.1E-4), and immune system response (P = 2.6E-4). This is consistent with the known biology of SIRS, which is a nonspecific host response to a variety of stresses, including trauma, surgery, and infection.A large number of genes were downregulated in H1N1 influenza A infection, bacterial infection, and SIRS groups (Figure (Figure1B).

1B). Biological pathway analysis of the downregulated genes was performed for each of the three patient phenotypes (Figure (Figure3).3). In the H1N1 influenza A group (934 unique genes), many genes were overrepresented in inflammatory-response and immune system-response pathways. Further interrogation into the immune-response pathways showed that activation and signaling pathways of interleukins (IL-8, IL-2, IL-15, IL-6, IL-10, IL-7, IL-3, IL-13, IL-17, and IL-23) were heavily overrepresented in the downregulated gene list. This suggests a significant degree of immunosuppression in severe H1N1 influenza A infection. In contrast, the degree of downregulation in biological pathways was considerably less in both the bacterial-infection and the SIRS groups (Figure (Figure33).

Figure 3Representation of biological pathway ontologies in the downregulated genes at 5% false discovery rate (FDR) for H1N1 influenza A, bacterial pneumonia, and systemic inflammatory response syndrome (SIRS), compared with healthy controls.Pathway analysis of the direct comparison between the H1N1 influenza A and bacterial groups revealed a consistent picture, with 671 genes upregulated in H1N1 influenza A compared with bacterial (by using linear mixed model, 5% FDR) showing remarkable overrepresentation in the cell cycle and its regulation ontology (P = 2.9E-20). The DNA-damage response was also highly enriched in this list of genes (P = 6.9E-10). No such overrepresentation was seen for cell-cycle pathways in the 78 genes expressed at higher levels in the bacterial infection group (P = 0.

35). The biological pathways overrepresented by these 78 genes include immune and inflammatory responses. However, these Cilengitide immune/inflammatory genes are also upregulated in SIRS and are therefore not specific to bacterial pneumonia.The immune cell subsets that gave rise to most of the gene-expression signals outlined earlier are shown in Figure Figure4,4, as revealed by immune cell deconvolution. Far more neutrophil-tagging genes were upregulated in the bacterial group compared with the H1N1 influenza A pneumonia (P = 2.