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Maren Depke Results Kidney Gene Expression Pattern in an in vivo Infection Model Table R.2.2: Tabular overview of infection-regulated genes which are included in Ingenuity Pathway Analysis (IPA, Ingenuity Systems, www.ingenuity.com) canonical pathway “Role of Pattern Recognition Receptors in recognition of Bacteria and Viruses” (modified from IPA, www.ingenuity.com). IPA Rosetta Resolver annotation fold change infection vs. sham infection localization and functional grouping a gene name gene name description EntrezGene ID RN1HG RN1HG ΔsigB extracellular PRR C1q C1qa complement component 1, q 12259 5.5 4.5 subcomponent, alpha polypeptide C1qb complement component 1, q 12260 7.4 6.0 subcomponent, beta polypeptide C1qc complement component 1, q 12262 6.9 5.4 subcomponent, C chain C3 C3 complement component 3 12266 5.1 5.1 membranebound C3aR C3ar complement component 3a receptor 1 12267 10.3 6.7 PRR C5aR C5ar complement component 5a receptor 1 12273 7.6 6.1 TLR1 Tlr1 toll-like receptor 1 21897 2.9 2.3 TLR2 Tlr2 toll-like receptor 2 24088 4.4 4.0 TLR4 Tlr4 toll-like receptor 4 21898 2.4 2.3 TLR6 Tlr6 toll-like receptor 6 21899 2.4 2.0 TLR7 Tlr7 toll-like receptor 7 170743 3.0 2.8 TLR8 Tlr8 toll-like receptor 8 170744 4.7 4.3 TLR9 Tlr9 toll-like receptor 9 81897 1.9 1.9 DECTIN-1 Clec7a C-type lectin domain family 7, member a 56644 3.7 2.8 cytoplasmic PRR NALP3 Nlrp3 NLR family, pyrin domain containing 3 216799 3.3 2.7 RIG-1 Ddx58 DEAD (Asp-Glu-Ala-Asp) box polypeptide 58 230073 1.7 1.6 MDA-5 Ifih1 interferon induced with helicase C domain 1 71586 1.5 1.3 signal PI3K Pik3cd phosphatidylinositol 3-kinase catalytic delta 18707 2.5 2.0 transduction, effector Pik3cg polypeptide phosphoinositide-3-kinase, catalytic, gamma 30955 3.4 3.1 molecules (cytoplasm) Pik3r5 polypeptide phosphoinositide-3-kinase, regulatory 320207 2.4 2.0 subunit 5, p101 MYD88 Myd88 myeloid differentiation primary response 17874 2.8 2.5 gene 88 SYK Syk spleen tyrosine kinase 20963 3.6 2.8 CASP1 Casp1 caspase 1 12362 3.4 2.2 IL-1β Il1b interleukin 1 beta 16176 29.0 21.5 OAS Oas1g 2'-5' oligoadenylate synthetase 1G 23960 2.2 1.7 Oas2 2'-5' oligoadenylate synthetase 2 246728 1.9 1.5 Oas3 2'-5' oligoadenylate synthetase 3 246727 1.7 1.4 RNaseL Rnasel ribonuclease L (2', 5'-oligoisoadenylate 24014 1.6 1.4 synthetase-dependent) transcription IRF-7 Irf7 interferon regulatory factor 7 54123 2.7 1.9 factors (nucleus) NFκB Nfkb1 nuclear factor of kappa light polypeptide 18033 2.0 1.9 gene enhancer in B-cells 1, p105 Nfkb2 nuclear factor of kappa light polypeptide 18034 2.7 2.5 gene enhancer in B-cells 2, p49/p100 transcriptionally TNFα Tnf tumor necrosis factor 21926 3.0 2.3 affected genes IL-6 Il6 interleukin 6 16193 9.2 7.8 RANTES Ccl5 chemokine (C-C motif) ligand 5 20304 6.9 4.9 a PRR – pattern recognition receptor Pattern recognition includes the complement system. The canonical pathway “Complement System” was significantly affected after infection (p = 6.86E−10; ratio = 16/36, Fig. R.2.8) which includes all three activation variants of classical, lectin and alternative pathway: The components C1q (C1qa, C1qb, C1qc), C1r (C1r, C1rb), C3, C4 (C4b), C7, Factor D / Adipsin (Cfd), Factor P / Properdin (Cfp), the complement-activating protease Masp1, and the receptors for C3a and C5a (C3ar, C5ar) were induced. A tendency of increased expression was observed for factors C2, C6, and Factor B (Cfb). But higher expression was also visible for the C1 inhibitor (Serping1), for the complement-inhibitory factor I (Cfi), and by trend for the inhibitory factor H (Cfh), probably as a reaction to restrict complement activation to a physiologically tolerable extent as the 84
Maren Depke Results Kidney Gene Expression Pattern in an in vivo Infection Model complement system can cause immense damage also to host cells and tissue. The complement component C8 consists of three chains (alpha, beta, and gamma) and is the last component in the C5b-C6-C7-C8 complex that acts as a catalyst in the polymerization of C9 to form the membrane attack complex MAC. Surprisingly, the gene C8a coding for the alpha chain was repressed in the infected samples, and also for the gene C8g (gamma chain) a tendency of repression was recorded. Possibly the opsonization and chemoattractant function of the complement system was enhanced in infection leading to phagocytosis, while the bacteriolytic function of the complement system was not potentiated. Otherwise, the components C8 and C9 – produced in the liver – might be delivered via the blood stream to the site of infection. Fig. R.2.8: Complement System (modified from IPA, www.ingenuity.com). Colors indicate direction and magnitude of differential regulation: red – induction; green – repression. More intense shade of color is used for higher absolute fold change values. A trend of induction is shown in yellow. Factor P / Properdin (CFP) has been inserted manually into the pathway. As already mentioned, the Toll-like receptor (TLR) signaling cascades lead to the transcription of different proinflammatory cytokines which themselves activate signaling pathways and the adequate cellular responses. When using the Canonical Pathways to specifically find infection relevant signal transduction, the signaling pathways of interferon, IL-6, TREM1, and IL-10 appeared among others with significant p-values. The pathway “Interferon Signaling” (p = 1.14E−06; ratio = 11/30; Fig. R.2.9) contains the induced IFN-γ receptor (Ifngr1, Ifngr2) and the IFNα/β-receptor, of which the gene for one of the two chains (Ifnar2) was induced, too. In the receptor’s signal transduction, the genes for signal transducers STAT 1 and 2 were induced together with the transcriptionally regulated genes Tap1, Ifitm1, Irf1, Psmb8, Irf9 and Oas1. Additionally, the inhibitory protein tyrosine phosphatase TC- PTP (Ptpn2) displayed a trend of induction, probably indicating a counter-regulatory process. 85
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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 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 Results Pathogen Gene E
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S. aureus RN1HG sample conditions a
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mean normalized intensity Maren Dep
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log 2 (ratio) log 2 (ratio) log 2 (
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Maren Depke D I S C U S S I O N A N
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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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