http://repub.eur.nl/res/aut/47981/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/34675/ 2011-04-11T00:00:00Z Background: Pneumonia represents a major health burden. Previous work demonstrated that although the induction of inflammation is important for adequate host defense against pneumonia, an inability to regulate the host's inflammatory response within the lung later during infection can be detrimental. Intracellular signaling pathways commonly rely on activation of kinases, and kinases play an essential role in the regulation of the inflammatory response of immune cells. Methodology/Principal Findings: Pneumonia was induced in mice via intranasal instillation of Streptococcus (S.) pneumoniae. Kinomics peptide arrays, exhibiting 1024 specific consensus sequences for protein kinases, were used to produce a systems biology analysis of cellular kinase activity during the course of pneumonia. Several differences in kinase activity revealed by the arrays were validated in lung homogenates of individual mice using western blot. We identified cascades of activated kinases showing that chemotoxic stress and a T helper 1 response were induced during the course of pneumococcal pneumonia. In addition, our data point to a reduction in WNT activity in lungs of S. pneumoniae infected mice. Moreover, this study demonstrated a reduction in overall CDK activity implying alterations in cell cycle biology. Conclusions/Significance: This study utilizes systems biology to provide insight into the signaling events occurring during lung infection with the common cause of community acquired pneumonia, and may assist in identifying novel therapeutic targets in the treatment of bacterial pneumonia. http://repub.eur.nl/res/pub/32357/ 2008-10-01T00:00:00Z Background: Macrophages and polymorphonuclear cells (PMNs) play an important role in the first line of defense against bacteria by infiltrating the infected organ in order to clear the harmful pathogen. Our earlier studies showed that granulocytes express type 3 deiodinase (D3) when activated during a turpentine-induced abscess. We hypothesized that D3 expression by granulocytes may also occur during bacterial infection. Methods: In order to test this hypothesis, we used the following experimental infection models: peritonitis induced by Escherichia coli and acute pneumonia induced by Streptococcus pneumoniae. Results: E. coli-induced peritonitis was characterized by infiltration in the liver by inflammatory cells with abundant immunocytochemical D3 expression while no staining was present in hepatocytes of infected or control mice. Acute pneumonia induced by S. pneumoniae resulted in inflamed lungs characterized by numerous infiltrating granulocytes expressing D3 while no D3 staining was present in lung sections without an infiltrate. Serum thyroid hormones were negatively correlated to bacterial outgrowth in both lung and spleen, and thus to the severity of illness. Conclusion: Infiltrating granulocytes during acute bacterial infection express D3. Our work supports the hypothesis that D3 plays an important role during chemical and bacterial inflammation. Whether the resulting decreased local bioavailability of thyroid hormones or rather the increased local availability of iodide is an important element of the innate immune response remains to be studied.