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Maren Depke Results Host Cell Gene Expression Pattern in an in vitro Infection Model Immune cells and other cells of the body are capable of presenting intracellular antigens via MHC-I. Although a significant increase in expression was observed for MHC-II gene HLA-DOP (3.8), all other MHC-II genes for both alpha and beta subunits were not differentially expressed. Additionally, the intensity of MHC-II gene expression is clearly among the lower values on the whole array. This is not surprising, because presentation of extracellular antigens via MHC-II preferentially occurs by professional antigen presenting cells (APC) like dendritic cells (DC), macrophages and B cells, and the human bronchial epithelial cell line S9, which was used in this study, does not belong to the group of professional APC. For the influence of staphylococcal infection on antigen presentation in in vivo kidney gene expression please refer to Results / Kidney Gene Expression Pattern in an in vivo Infection Model / Fig. R.2.12, page 88. Persistence and enhancement of S9 reaction to infection with S. aureus RN1HG from the 2.5 h to the 6.5 h time point It has already been mentioned that a big fraction of the genes, which were differentially expressed at the 2.5 h time point, was still regulated at the later 6.5 h time point. This concerned 26 genes (Table R.4.5). Table R.4.5: Overview on genes which were differentially expressed in S9 cells at both the 2.5 h and the 6.5 h time point in comparison between infection with S. aureus RN1HG GFP and control treatment. Rosetta Resolver annotation fold change a gene name description Entrez Gene ID 2.5 h 6.5 h IL6 interleukin 6 (interferon, beta 2) 3569 4.2 11.9 NFKBIZ nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, zeta 64332 3.0 7.9 IFNB1 interferon, beta 1, fibroblast 3456 2.8 3.6 IFIT2 interferon-induced protein with tetratricopeptide repeats 2 3433 2.4 5.2 PTGS2 prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase) 5743 2.3 1.6 KLF4 Kruppel-like factor 4 (gut) 9314 2.1 9.9 ATF3 activating transcription factor 3 467 2.1 3.9 PPP1R15A protein phosphatase 1, regulatory (inhibitor) subunit 15A 23645 2.1 2.4 EDN1 endothelin 1 1906 2.0 8.2 NEDD9 neural precursor cell expressed, developmentally down-regulated 9 4739 2.0 5.5 PMAIP1 phorbol-12-myristate-13-acetate-induced protein 1 5366 2.0 4.4 PTGER4 prostaglandin E receptor 4 (subtype EP4) 5734 1.8 5.2 ADAMTS1 ADAM metallopeptidase with thrombospondin type 1 motif, 1 9510 1.8 -1.7 BCL6 B-cell CLL/lymphoma 6 604 1.7 3.5 SAT1 spermidine/spermine N1-acetyltransferase 1 6303 1.6 4.6 ZFP36L2 zinc finger protein 36, C3H type-like 2 678 1.6 4.0 FAM46A family with sequence similarity 46, member A 55603 1.6 3.5 IFIT3 interferon-induced protein with tetratricopeptide repeats 3 3437 1.6 3.4 TNC tenascin C 3371 1.6 2.1 LIF leukemia inhibitory factor (cholinergic differentiation factor) 3976 1.6 2.2 CD274 CD274 molecule 29126 1.6 5.5 KLF6 Kruppel-like factor 6 1316 1.5 2.6 ZC3H12C zinc finger CCCH-type containing 12C 85463 1.5 2.8 C6orf141 chromosome 6 open reading frame 141 135398 1.5 3.7 CDCA8 cell division cycle associated 8 55143 -1.5 -2.1 HIST1H2AB histone cluster 1, H2ab 8335 -1.6 -2.1 a Fold change values were calculated for the comparison of infected GFP + S9 cell with the baseline of medium control samples. Leukemia inhibitory factor (LIF) was already increased 2.5 h after start of infection (fold change 1.6). This increase was further elevated after 6.5 h (2.2). Fittingly, increased expression was also detectable for the LIF receptor (LIFR, 2.2) at this time point. 122
Maren Depke Results Host Cell Gene Expression Pattern in an in vitro Infection Model CD274 alias programmed cell death 1 ligand 1 (PD-L1) is involved in the regulation of inflammatory responses (Sharpe et al. 2007). In this study, CD274 gene expression was induced 2.5 h after start of infection and further increased at the 6.5 h time point. Interestingly, at the later time point, the second PD-1 receptor, programmed cell death 1 ligand 2 (PDCD1LG2; 2.7), was also induced. The prostaglandin-endoperoxide synthase 2 (PTGS2) was less induced at the 6.5 h than at the 2.5 h time point (Table R.4.5). Additionally, the intensity values for PTGS2 at 6.5 h were lower in both control and infected samples (60 and 94) when compared to the 2.5 h control sample (280). This might hint for an early reaction that was about to stop at the later time point. Induction of prostaglandin receptor PTGER4 still increased from 2.5 h to 6.5 h, and induction of another receptor, PTGER2, was only detectable at the 6.5 h time point. The reaction of the genes for these receptors seemed to lag behind the reaction of the gene coding for the enzyme responsible for synthesis of their ligand. Interferon-β (IFNB1) was induced at both analyzed time points. At the 2.5 h time point, interferon reaction has already been described in reference to the induced genes IFIT2 and IFIT3 (page 117). In the IPA canonical pathway “Interferon Signaling” (page 119), IFI35, IFIT1, IFIT3, IRF1, and others were included as induced, interferon-regulated genes at the 6.5 h time point, and IFIH1 has already been introduced in the IPA canonical pathway “Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses” (page 120). Manual filtering revealed further six interferon regulated genes IFI16, IFI44L, IFIT2, IFIT5, IRF2, and ISG20 to be induced 6.5 h after start of infection. A histone cluster 1 gene (HIST1H2AB) was repressed significantly with a less than −1.5x fold change 2.5 h after start of infection. But 6.5 h after infection, a number of 17 other histone cluster 1 genes together with HIST1H2AB were repressed. Of these 17 additional genes, 4 had already yielded a significant p-value at the 2.5 h time point, but did not pass the 1.5 fold cutoff. Furthermore, H1 histone family member 0 (H1F0) and H2A histone family member X (H2AFX) were repressed at the 6.5 h time point (Table R.4.5, Table R.4.6). Cyclins CCNB1, CCNB2, and CCNH were repressed, while CCND1 and CCNL1 were induced 6.5 h after start of infection. In this context, induced cyclin-dependent kinases / kinase-like CDK6, CDKL2, and CDKL5 were conspicuous at the 6.5 h time point, while cyclin-dependent kinase inhibitors CDKN1B, CDKN2B, and CDKN3 were repressed. Contrarily, the inhibitor CDKN2C was induced. Similarly, genes coding for cell division cycle associated proteins CDCA3, CDCA4, CDCA8, and CDC25A, and genes encoding centromer/centrosomal proteins CENPF, CEP55, CEP97, CEP120, and CEP250 were repressed, while CDC14A and CEP170 were induced. Regulatory genes CKS2, GAS2L3, PRC1, and SKP2 were repressed, whereas BTG1, CHEK2, and DMTF1 were observed as induced (Table R.4.6). In a condensed manner, histones were repressed, some cyclin-dependent kinase (CDK) were induced, and CDK inhibitors, cyclins, cell division cycle associated proteins, centromer/ centrosomal proteins and regulatory genes were found with both repressed and induced examples. Nevertheless, repression held a bigger fraction of this subset of genes than induction. 123
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G E N O M E W I D E C H A R A C T E
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Maren Depke C O N T E N T S GENOMEW
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Maren Depke Z U S A M M E N F A S S
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Maren Depke Zusammenfassung der Dis
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Maren Depke S U M M A R Y O F D I S
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Maren Depke Summary of Dissertation
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Maren Depke I N T R O D U C T I O N
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Maren Depke Introduction Besides op
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Maren Depke Introduction Extracellu
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Maren Depke Introduction with heigh
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Maren Depke Introduction 2005). SaP
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Maren Depke Introduction contains a
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Maren Depke Introduction via fibron
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Maren Depke Introduction cathelicid
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Maren Depke Introduction shock are
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Maren Depke Introduction STUDIES OF
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Maren Depke Introduction are effect
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Maren Depke Introduction cell stimu
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Maren Depke Introduction channel CF
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Maren Depke M A T E R I A L A N D M
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Maren Depke Material and Methods Li
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Maren Depke Material and Methods Ki
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Maren Depke Material and Methods GE
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Maren Depke Material and Methods Ho
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Maren Depke Material and Methods Pa
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corticosterone [pg/ml plasma] corti
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Maren Depke Results Liver Gene Expr
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lood glucose levels [nmol/l] resist
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LBP [ng/ml] CPR [ng/ml] Maren Depke
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Maren Depke Discussion and Conclusi
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Maren Depke References Athanasopoul
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Maren Depke References Byrne GI, Le
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Maren Depke References Demling R. T
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Maren Depke References Foss GS, Pry
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Maren Depke References Hagopian K,
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Maren Depke References Jin T, Bokar
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Maren Depke References Kwan T, Liu
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Maren Depke References Luster AD, U
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Maren Depke References Namiki S, Na
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Maren Depke References Puccetti P.
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Maren Depke References Siewert E, B
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Maren Depke References van den Akke
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Maren Depke References Yang XL, Sch
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Maren Depke A F F I D A V I T / E R
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Maren Depke Acknowledgments Kidney
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