virus-host interaction
E. Derm cells were infected with (A) O/03 and (B) U/63-WT and mutant viruses or mock infected for 8 h The percentage of cells expressing the viral nucleoprotein among live cells and total cell viability was
6.2.2. Transcriptome of O/03 wild-type and mutant virus-infected cells 1 Degree of dissimilarity between samples
6.2.2.5. Top canonical signalling pathways modified by O/03 viruses To identify possible biological interactions of DEGs and important functional
networks, the sets of genes with altered expression in O/03-WT and mutant virus infected cells were imported into the Ingenuity pathway analysis (IPA) tool. As seen in (Figure 6-12), the O/03-WT virus activated a larger number of pathways compared to mutant viruses. Infection with this virus was associated with up-regulation of genes involved in cell survival, such as the PI3K/AKT pathway, and down-regulation of genes associated with cell cycle arrest and cell death (i.e. apoptosis signalling, telomerase signalling, cell cycle G1/S checkpoint regulation, p53 signalling, role of BRCA1 in DNA damage response, cell cycle G2/M checkpoint regulation). Some inflammatory pathways were also downregulated in these cells (i.e. IL-17A signalling in airway cells, IL-6 signalling, LXR/RXR activation or TNFR1 signalling), while other were activated (i.e. LPS/IL-1 mediated inhibition of RXR function, FceRI signalling, IL-8 signalling) (Al-Garawi et al., 2012).
In addition, in O/03 mutant virus-infected cells several key innate immune receptor pathways involved in virus sensing were activated, such as interferon signalling, activation of IRF by cytosolic pattern recognition receptors, RIG-I-like receptors and antiviral innate immunity, or pattern recognition receptors of bacteria and viruses.
Figure 6-12: Top canonical signalling pathways activated by O/03-WT and mutant viruses. The Ingenuity Pathway Analysis (IPA) tool was used to generate a list of significant canonical pathways activated in virus-infected cells compared to mock-infected cells based on the lists of transcripts found as significantly differentially expressed compared to mock-infected cells.
The U/63 WT and mutant-infected samples were analysed in a similar fashion to O/03- infected samples.
EIF2 Signaling SAPK/JNK Signaling LPS/IL-1 Mediated Inhibition of RXR Function PPARα/RXRα Activation ATM Signaling HGF Signaling RhoGDI Signaling Cyclins and Cell Cycle Regulation HMGB1 Signaling Protein Kinase A Signaling PTEN Signaling Fc Epsilon RI Signaling Antiproliferative Role of Somatostatin Receptor 2 Calcium Signaling Ceramide Signaling cAMP-mediated signaling Ephrin Receptor Signaling PI3K/AKT Signaling IL-8 Signaling Interferon Signaling Death Receptor Signaling Activation of IRF by Cytosolic Pattern Recognition Receptors Role of RIG1-like Receptors in Antiviral Innate Immunity ILK Signaling Rac Signaling IL-17A Signaling in Airway Cells JAK/Stat Signaling p70S6K Signaling Regulation of eIF4 and p70S6K Signaling AMPK Signaling CXCR4 Signaling NGF Signaling IL-6 Signaling ERK/MAPK Signaling mTOR Signaling Signaling by Rho Family GTPases Gαq Signaling NF-κB Activation by Viruses Telomerase Signaling Cell Cycle: G1/S Checkpoint Regulation p53 Signaling NRF2-mediated Oxidative Stress Response Role of BRCA1 in DNA Damage Response LXR/RXR Activation PDGF Signaling Cell Cycle: G2/M DNA Damage Checkpoint Regulation TNFR1 Signaling Neurotrophin/TRK Signaling PPAR Signaling Actin Cytoskeleton Signaling Growth Hormone Signaling Integrin Signaling O/ 0 3 -WT O/ 0 3 -230 O/ 0 3 -K1 8 6 E -23 0 O/ 0 3 -K1 8 6 E 0 IFIT3 5_8S_rRNALYRM7 ENSECAG00000004574TYSND1CH25HIFIT1LSS
ENSECAG00000019576AGER ENSECAG00000005401C3orf14EFNB2CXCL8RSRP1PTGS2EGR1 ENSECAG00000005903ATP5EP2ITGB3BPCHCHD7TPRKBPIGW ENSECAG00000027699FAM175AGCSHSSB ENSECAG00000011843MRPS18CADAM33RPL22L1UBXN2AGTPBP3SCARF2UNC5BAPBB3ARPC3RPS24CMC1ISCA1SKA1LY96ND1ND4 ENSECAG00000007112SLC16A13OPLAHU3 ENSECAG00000019095 ENSECAG00000027676 ENSECAG00000016730SERPINB2CENPK ENSECAG00000016459POLRMTMESDC1ZFP36L1COL7A1MEGF6CHAC1DDIT4BRAT1SESN2TRIB3FASN ENSECAG00000011475TMSB4XPOLR2KC8orf59SPA17TBCASPX ENSECAG00000008688
ENSECAG00000019932GADD45ASEMA3AMSMO1IGFBP4EPSTI1DDX60IFIH1PI3 ENSECAG00000010185 ENSECAG00000025328 ENSECAG00000000968 ENSECAG00000027056SAMD9L ENSECAG00000021220EIF2AK2SAMD9RSAD2PARP9ISL1 ENSECAG00000010566MVDLDLR NEXN IL22RA1ELOVL6ABCA1FIBINSCD HMGCS1DHX58IFI44LISG15IFI44LIPG ENSECAG00000000284MX1 ENSECAG00000012132OAS2IFI35IRF9 ENSECAG00000014226C17orf98FAM26DFDFT1ACSS2SGPP2TEX43MVK7SK ENSECAG00000027680FERMT3FCER1GTAGLN3ACTA1PYGMSV2AGPR1CPE ENSECAG00000019367ANKRD35CDO1 ENSECAG00000006922PPP1R27PNLDC1ZNF619ZNF514THSD1CHRNETSSK3 ENSECAG00000009142 ENSECAG00000020764ZNF454HBEGFSTAR ENSECAG00000020952PTPN22RGS2CSF3 ENSECAG00000021582CASP12FBXO48AVILIL5 ENSECAG00000014572 ENSECAG00000003681FAM200BN4BP2L1ITGA10DYRK4LEAP2SYCP2 ENSECAG00000013527HLA-DMAFAM122CCCDC169ZCCHC10SLITRK4KBTBD3GPR19CREG2HSPH1KRT25IQUB ENSECAG00000002021TMEM154COMMD8CCDC121SUV39H2CCDC126MTRF1LDEPDC7HACD1GNG11PDE4BPTGR1TLR10CHSY3EDN1TPMTTIPINE2F5 ENSECAG00000013255FAM184BBCAP29MAP9HNMTLMLNTNIP3FGF7TANKSTX2 ENSECAG00000016351CYP7B1ZC3H8ZNF25 ENSECAG00000010696SERPINB10ATP6V1E1FAM161AC1orf189ZNF280CCHMP2BMRPS36TXNDC9CACYBPCCDC58CCDC59NUCB2MCTS1ZBTB11THAP2MEIOCSNRPGRFESDCEP83SYTL2SKIL ENSECAG00000002943SPATA33CWH43CETN3FOXN2 ENSECAG00000010323LAMTOR3CEP57L1CCDC62LYPLA1ERCC6LN4BP2UEVLDFGF12BCAS2AK6 ENSECAG00000015459PIBF1CLK1 ENSECAG00000018554RPL36ALC11orf1GLRX2 ENSECAG00000005764NDUFAF6ARRDC3HRSP12RWDD1THAP6GKAP1CCSAPCRLS1RPL26EIF3JNIFK ENSECAG00000018693ZNF614DTWD1ZNF674TIMM9UQCRBRPL21TAF1DLSM3HAT1 ENSECAG00000016758MGAT4ASSBIP1LIPT1 ENSECAG00000015373DYNC2LI1FAM105AOSGEPL1SLC12A9RHBDD3NDUFS7OCIAD1KLHL17SLC1A5GMNNSep-10PHF11SUB1TXN ENSECAG00000014263GMPPARHOB ENSECAG00000008220WNT10BMARCKSWDR83DYRK1BZNF414LAMA5MFSD3SHISA5DDAH2PRKD2HSPG2NLRC5LPAR2BCL9LDGKQDDR1TSPOASB9FUKEFS ENSECAG00000017916IGFLR1 ENSECAG00000015936 ENSECAG00000012571METTL12FAAP100DPYSL4EPHX3DHX34MBD6AP5Z1MIEF2KLRG2TBCC ENSECAG00000026952TMEM132AARHGAP39GADD45GFAM212AFAM110ATP53INP2C1QTNF5TMEM8BC19orf54PLEKHG4KAZALD1SLC27A5PPP1R35TSC22D4NEURL2ZNF688COL5A1COL5A3NFATC4ZNF219LRRC73PROM2KCTD11COL4A2MFSD7ARMC5MEGF8SPTSSASHISA4PLPPR2HS3ST1TOR4AGPR39ATG9BCDH15NXPH4NAPRTPTRH1FOXG1EEPD1TAPBPWISP2PELP1SPHK2TRIP6RELL2TYMPLTBP4XKR8SDC3FUT1SDSLYDJCMNTERF
ENSECAG00000013867SERTAD4MBLAC1CARNS1KCTD7 ENSECAG00000011161WBSCR27SLC25A29NANOS1TNFAIP2PCSK1NSLC2A4KMT5CATG4DFANCFCTU1NPPBFHL1 ENSECAG00000021748PLAC8GBP2IRS2 ENSECAG00000004306SLC15A3RNF213HERC6DTX3LOAS3 ENSECAG00000002176ZC3HAV1AXDND1CMPK2DDX58HERC5UBE2NOAS1 ENSECAG00000001514PARP12 ENSECAG00000020384 ENSECAG00000006930 ENSECAG00000023195COL18A1MFSD2ASCAND1TRIM47FBXW9FBXL6SCO2IFIT5 ENSECAG00000017795TMEM223MID1IP1FAM46BJUNBMSCNGF ENSECAG00000004050ACVR2A ENSECAG00000024319STOML1MRPS12TICAM1ARID3AATF4 ENSECAG00000014783TRMT61ASNAPC2ENTHD2ARRDC2WNT9AREPIN1APBA3IER3 ENSECAG00000024986MAP1SRRS1 ENSECAG00000022294C14orf80NUDT14DUS3LDOHHHMX3MIDNMIIPBCL3IRX2 ENSECAG00000010803TRIM62SOCS1 ENSECAG00000022195C19orf52TRABD2BSH2D5 ENSECAG00000024586ADAMTS15PLEKHH3CEBPZOSCCDC120LSMEM1TM7SF2SPATA2LCDKN2BGPRC5ACDKN2ASWSAP1LRRC66OBSCNGFOD1NACC2PDAP1LYRM4HSPA6ATP5DRPL19AKNATNXBCBX4RIN1RELBFJX1IL11HLX ENSECAG00000002024CALD1CARD9PTMA ENSECAG00000008785ATP6V1G1TRAF3IP1SNRNP27SREK1IP1ZC3H13HMGB2INCENPLMOD1HMMRRBMX2ZMAT2HIRIP3CLSPNBASP1SPAG7PSIP1HYPKTCHP ENSECAG00000008385FAM133BMYEOV2CCDC12HMGA1DNAJC8LUC7L3CDCA8NUDCPCNPENSAGPS2 ENSECAG00000026980 ENSECAG00000008928CENPF ENSECAG00000003089GADD45GIP1FAM50AGOLIM4CFAP45SRRM1MFAP1RBM25SUDS3C8orf4TPM1PTN ENSECAG00000003616C1orf131CCDC150MYH11RNPS1PDCD7MURCTCF7 ENSECAG00000019569NUPR1KRT23LYAR ENSECAG00000013815 ENSECAG00000007123 ENSECAG00000019621PSMC3IPGOLM1UPF3BSRSF4E2F7 ENSECAG00000021271RAD51AP1C9orf78HAUS8ATPIF1ACIN1TNIP1PYM1BRD3DEK ENSECAG00000013512MAD1L1NUSAP1CEP152UPF3AKIF15ODF2TPX2BIN3 ENSECAG00000002115 ENSECAG00000008466POLD3RPL37PPIGING1 ENSECAG00000024902NDUFB10SUMO2PRR11SLU7 ENSECAG00000015496 ENSECAG00000007487CCDC136MAP7D3MESDC2CKAP2LMEAF6NSRP1ZWINTLENG1SEC62CEP85IK ENSECAG00000022285SPECC1NUP62TXLNACEP55PPL ENSECAG00000012023C14orf119PPP1R14BSLC25A33C11orf58CHMP4APPP3CBRNF11AMOTTPM2PTENLLPHPKIA ENSECAG00000023284CCNG2NR4A2TGDSUBL3CD9HGFAGL ENSECAG00000002481TSC22D3HOXA10 ENSECAG00000010827PTBP2 ENSECAG00000005757FAM174AC14orf28HSD17B7SLC38A6CYP39A1CYP51A1LURAP1LTXNDC8FAM13CCTNNA2STARD4RNF139HMGCRATRNL1FLVCR1RAP2CEFNA5GPR12CASD1SQLESC5D ENSECAG00000003658 ENSECAG00000006174SNX21 ENSECAG00000027451IL36G ENSECAG00000027624IRF8 ENSECAG00000014398TMEM126BRUNDC3BS100A12IL13RA2ARNTL2CENPQMYBL1CCNE2PFDN4SNRPFMSR1FBXL2CD58SV2BVRK1COX2TFPI2ND2F3 ENSECAG00000020878TROAPPQLC1CHST3CLIP2 ENSECAG00000007907ARHGAP33CATSPERDALDH1A3TBC1D2BCL11BSORCS2SNTB1OBSL1CPLX2AZIN2FEZF2NOD1REM1SEZ6DLL1 ENSECAG00000013783U6 -6 -4 -2 0 2 4 63 -3 z-score -1 -2 1 2
Figure 6-11: Top canonical signaling pathways activated by O/03-WT and mutant viruses.
The Ingenuity pathway analysis (IPA) tool was used to generate a list of significant canonical pathways activated in virus-infected samples compared to mock-infected samples based on the lists of transcripts found as differentially expressed compared to the mock-infected conditions with Log2FC³0.58 and p value<0.05.