Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Streptococcus pneumoniae, the major cause of community-acquired pneumonia and bacterial meningitis, has been shown to transiently invade epithelial and endothelial cells. Innate immune receptors including Toll-like receptors recognize various pathogens, such as S. pneumoniae, by identifying conserved pathogen-associated molecular patterns. Recently, two members of a novel class of pattern recognition receptors, the cytosolic proteins nucleotide-binding oligomerization domain 1 (Nod1)/CARD4 and Nod2/CARD15, have been found to detect cell wall peptidoglycans. Here we tested the hypothesis that Nod proteins are involved in the intracellular recognition of pneumococci. Data indicate that pneumococci invade HEK293 cells. Genetic complementation studies in these cells demonstrate that NF-kappaB activation induced by S. pneumoniae depends on Nod2. Moreover, intracellular transfection of inactivated pneumococci yielded similar effects, confirming the Nod2 dependence of NF-kappaB activation by pneumococci in HEK293 cells. By dominant negative overexpression and small interfering RNA experiments, we show for the first time that interleukin-1 receptor-associated kinase participates in Nod2-dependent NF-kappaB activation. Additionally, dominant negative interleukin-1 receptor-associated kinase 2, tumor necrosis factor receptor-associated factor 6, NF-kappaB-inducing kinase, transforming growth factor-beta-activated kinase-binding protein 2, and transforming growth factor-beta-activated kinase 1 also inhibited Nod2-dependent NF-kappaB activation. We finally demonstrate that in C57BL/6 mouse lung tissue in vivo as well as in the bronchial epithelial cell line BEAS-2B, Nod1 and Nod2 mRNA expressions were up-regulated after pneumococcal infection. Data presented suggest that Nod proteins contribute to innate immune recognition of S. pneumoniae. Furthermore, Rip-2 and members of the Toll-like receptor-signaling cascade are involved in the Nod2-dependent activation of NF-kappaB induced by pneumococci.
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PMID:Nucleotide-binding oligomerization domain proteins are innate immune receptors for internalized Streptococcus pneumoniae. 1521 47

Gram-positive bacterium Streptococcus pneumoniae is an important human pathogen that colonizes the upper respiratory tract and is also the major cause of morbidity and mortality worldwide. S. pneumoniae causes invasive diseases such as pneumonia, meningitis, and otitis media. Despite the importance of pneumococcal diseases, little is known about the molecular mechanisms by which S. pneumoniae-induced inflammation is regulated, especially the negative regulatory mechanisms. Here we show that S. pneumoniae activates nuclear factor of activated T cells (NFAT) signaling pathway and the subsequent up-regulation of inflammatory mediators via a key pneumococcal virulence factor, pneumolysin. We also demonstrate that S. pneumoniae activates NFAT transcription factor independently of Toll-like receptors 2 and 4. Moreover, S. pneumoniae induces NFAT activation via both Ca(2+)-calcineurin and transforming growth factor-beta-activated kinase 1 (TAK1)-mitogen-activated protein kinase kinase (MKK) 3/6-p38alpha/beta-dependent signaling pathways. Interestingly, we found for the first time that tumor suppressor cylindromatosis (CYLD) acts as a negative regulator for S. pneumoniae-induced NFAT signaling pathway via a deubiquitination-dependent mechanism. Finally, we showed that CYLD interacts with and deubiquitinates TAK1 to negatively regulate the activation of the downstream MKK3/6-p38alpha/beta pathway. Our studies thus bring new insights into the molecular pathogenesis of S. pneumoniae infections through the NFAT-dependent mechanism and further identify CYLD as a negative regulator for NFAT signaling, thereby opening up new therapeutic targets for these diseases.
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PMID:Tumor suppressor cylindromatosis acts as a negative regulator for Streptococcus pneumoniae-induced NFAT signaling. 1833 37