Outbreaks of appearing and reappearing of SARS-CoV-2 infection are frequent threats to human health across globe. When a novel virus was detection and linked with human disease, it is necessary to understand molecular pathogenesis of SARS-CoV-2 infection as soon as possible to progress treatment to the disease such as vaccines and antiviral drugs [49]. In this investigation, we performed a series of bioinformatics analysis to screen hub genes and pathways associated with SARS-CoV-2 infection. The expression profiling by high throughput RNA sequencing found that 49 up regulated genes and 72 down regulated genes were identified in remdesivir traded SARS-CoV-2 infection compared to non treated SARS-CoV-2 infection. Genes such as IRF7 [50], MX2 [51], TRIM25 [52], TRIM14 [53], IFIT5 [54] and IFIT1 [55] were liable for progression of influenza virus infection, but these genes may be responsible for advancement of SARS-CoV-2 infection. Genes such as OAS3 [56], OASL (2'-5'-oligoadenylate synthetase like) [57] and USP18 [58] were linked with progression of various viral infections, but these genes may be key for progression of SARS-CoV-2 infection. RSAD2 was involved in pathogenesis of measles virus infection [59], but this gene may be associated with progression of SARS-CoV-2 infection.
The ToppGene online tool was used to perform a pathway enrichment analysis. DDX58 was involved in the progression of measles virus infection [60], but this gene may be linked with advancement of SARS-CoV-2 infection. Enriched genes such as CIITA (class II major histocompatibility complex transactivator) [61], CCL2 [62], PML (promyelocyticleukemia) [63], ICAM1 [64], IL1A [65], MX1 [66], CXCL8 [67], MYD88 [68], CXCL10 [69], STAT1 [70], STAT2 [71], SOCS3 [72], CASP1 [73], TLR3 [74], TNF (tumor necrosis factor) [75], IL32 [76], TRIM22 [77], IFITM3 [78], FGF2 [79], IFITM1 [80], IFITM2 [81], IFI27 [82], ISG15 [83], SOCS1 [84], IRF1 [85], ISG20 [86], IL22RA1 [87], SOCS2 [88], GBP5 [89], BST2 [90], HERC5 [91], IL27 [92], CXCL13 [93], CXCL3 [94], TLR2 [95] and TNFAIP3 [96] were liable for development of influenza virus infection, but these genes may be essential for progression of SARS-CoV-2 infection. Enriched genes such as CCL5 [97], IL19 [98], CCL3 [97], CCL4 [99], CCL20 [100], IFIT3 [101], CSF3 [102] and IL7R [103] were important for development of respiratory syncytial virus infection, but these genes may be liable for advancement of SARS-CoV-2 infection. Enriched genes such as IL6 [104] and JAK2 [105] were responsible for progression of SARS-CoV-2 infection. Enriched genes such as TICAM1 [106], OAS1 [107], OAS2 [108], CXCL9 [109], EREG (epiregulin) [110], CCL22 [111], VCAM1 [112], IFI35 [113], IFIT2 [114], TRIM5 [115], XAF1 [116], IFI6 [117], IL7 [118], SP100 [119], GBP1 [120], GBP2 [121], IRF4 [122], MIR5193 [123], IFNL3 [124], CYP21A2 [125], CXCL5 [126], CX3CL1 [127], CCL4L1 [128], WNT16 [129], GNB3 [130], FLG (filaggrin) [131] and HEY1 [132] were responsible for progression of various viral infections, but these genes may be involved in the development of SARS-CoV-2 infection. Expression of NOS2 was associated with development of rhinovirus infection [133], but this gene may be involved in progression of SARS-CoV-2 infection. Expression of CCR1 was liable for progression of pneumovirus infection [134], but this gene may be linked with advancement of SARS-CoV-2 infection. Expression of IRAK2 was important for progression of bronchitis virus infection [135], but this gene may be involved in development of SARS-CoV-2 infection. In general, the our findings suggested that novel biomarkers such as SCO2, TYMP (thymidine phosphorylase), HSPA6, IFNB1, IKBKE (inhibitor of nuclear factor kappa B kinase subunit epsilon), EIF2AK2, TNFSF10, TNFRSF10A, IFIH1, IL23A, UBE2L6, HLA-F, RASGRP3, TRIM38, BATF (basic leucine zipper ATF-like transcription factor), NRG2, BIRC3, MT2A, CSF1, TNFSF13B, IL15RA, GBP7, IL36A, IL17C, PSMB9, TNFRSF6B, GBP3, TRIM21, PTGS2, GBP4, BTC (betacellulin), TNFSF18, HBEGF (heparin binding EGF like growth factor), DUSP5, TRIM31, RET (ret proto-oncogene), CXCL2, TRIM10, LGALS9, LIF (LIF interleukin 6 family cytokine), LIFR (LIF receptor subunit alpha), EBI3, IL36G, HCK (HCK proto-oncogene, Src family tyrosine kinase), IFNL2, IFNL1, HSD11B1, CXCL11, S100A7A, ANGPTL1, KLHL23, PDXP (pyridoxal phosphatase), ADH1A, ADH1C, ADH6, GSTA5, ALDH3B1, FMO5, GSTT2, PTCH2, IHH (Indian hedgehog signaling molecule), CDON (cell adhesion associated, oncogene regulated), F2R, TAS2R50, WNT8B, WNT9A, OXGR1, PTGFR (prostaglandin F receptor), TACR1, GPER1, GRM4, CCKBR (cholecystokinin B receptor), OPRL1, RLN2, TAS1R1, ALDH3A2, GDF5, FGF9, EGFL6, FGF22, INHA (inhibin subunit alpha), INHBC (inhibin subunit beta C), GDF7, FGFBP3, BMP15, HES5, LFNG (LFNG O-fucosylpeptide 3-beta-N-acetylglucosaminyltransferase), HEYL (hes related family bHLH transcription factor with YRPW motif like), SULT1E1 and SULT2B1 may play key roles in the action mechanism of SARS-CoV-2 infection.
The functions of the up and down regulated genes were identified by GO enrichment analysis. Enriched genes such as TREX1 [136], IFNL4 [137], MICB (MHC class I polypeptide-related sequence B) [138], RAB43 [139], APOL1 [140], IFI16 [141], APOBEC3B [142], SLAMF7 [143], HDAC9 [144], APOBEC3A [145], SERPING1 [146], TAP2 [147], LAG3 [148], OPTN (optineurin) [149], CD68 [150], SP140 [151], PDCD1 [152], PLVAP (plasmalemma vesicle associated protein) [153], CD34 [154], CD38 [155], CD69 [156], SLC30A8 [157] and ATP6V1G2 [158] were liable for progression of various viral infections, but these genes may be involved in the progression of SARS-CoV-2 infection. Enriched genes such as APOBEC3G [159], ADAM8 [160], ZBP1 [161], NLRC5 [162], AIM2 [163], DUOX2 [164], NOX1 [165], IDO1 [166], CEACAM1 [167], PTX3 [168], TAP1 [169], FFAR2 [170] and E2F1 [171] were linked with progression of influenza virus infection, but these genes may be associated with progression of SARS-CoV-2 infection. CD83 was responsible for advancement of respiratory syndrome virus [172], but this gene may be essential for development of SARS-CoV-2 infection. ACE2 was linked with progression of SARS-CoV-2 infection [173]. NMI (N-myc and STAT interactor) was liable for progression of severe acute respiratory syndrome corona virus [174], but this gene may be important for development of SARS-CoV-2 infection. CD274 was associated with progression of rhino virus infection [175], but this gene may be essential for progression of SARS-CoV-2 infection. In general, the our findings suggested that novel biomarkers such as PIK3AP1, NT5C3A, NCF1, TNIP3, CLEC1A, CLEC7A, DTX3L, MEF2C, MEP1B, ADM (adrenomedullin), SAA2, SAA4, SERPINB9, MUC17, ABCD1, APOL2, PLSCR1, PMAIP1, FOXF1, DUOXA2, THEMIS2, ZC3H12A, DHX58, DDX60, C2CD4A, MUC13, PARP14, BATF2, PLA2G4C, NUB1, STX11, ZC3HAV1, TAGAP (T cell activation RhoGTPase activating protein), RNF19B, GCH1, PTGIR (prostaglandin I2 receptor), RTP4, ARID5A, TMEM106A, PRDM1, DEFB4A, IFIT1B, C1R, C1S, C3AR1, PARP9, IFI44L, HERC6, ICOSLG (inducible T cell costimulator ligand), TRIM15, NUPR1, TGM2, APOL3, TNFAIP6, MAPK8IP2, ACHE (acetylcholinesterase (Cartwright blood group)), CHRNA1, FZD9, PLAUR (plasminogen activator, urokinase receptor), SELL (selectin L), ACKR4, PDCD1LG2, KCNA1, SECTM1, WIPF3, APELA (apelin receptor early endogenous ligand), THEG (theg spermatid protein), PKDREJ (polycystin family receptor for egg jelly), TFCP2L1, TDRD6, TXNDC8, ZFP37, RIMBP3, NLRP14, FMN2, RIMBP3B, MYBL1, ZBTB16, INHBB (inhibin subunit beta B), NDP (norrincystine knot growth factor NDP), GGT3P, STOX2, GJB1, SOHLH2, BUB1B, DLX3, RAB3A, CBX2, GPR3, SPATA31A3, DPY19L2, BCL2L10, SOX30, E2F8, RLN1, VASH2, SLC29A3, CACNA2D2, PKD1L2, TMC3, AMIGO1, TRPM3, HPX (hemopexin), AKAP6, KCTD7, NLGN1, SLC47A2, SLC32A1, SLC9A2, TMEM37, CACNG4, ATP6V1B1, SLC46A1, SLC30A2, GPD1L, PPARGC1A, KCNF1, TMEM150C, CACNA1D, AQP10, CACNG1, SLC52A1, SLC16A9, HCN4, NGB (neuroglobin), TMEM63C, ABCC5, P2RX6, SLC16A14, SLC25A19 and SLC29A1 may play key roles in the action mechanism of SARS-CoV-2 infection.
The construction of protein-protein interaction network and module analysis for up and down regulated genes, has been proven to be useful in the analysis of hub genes involved in SARS-CoV-2 infection. HELZ2 was associated with development of dengue virus infection [176], but this gene may be liable for progression of SARS-CoV-2 infection. BATF3 was involved in advancement of respiratory poxvirus infection [177], but this gene may essential for development of SARS-CoV-2 infection. In general, our findings suggested that novel biomarkers such as FBXO6, SBK1, ARL14, LMO2, LAP3, TFAP4, APBB1, ELF5, USP2, ERP27, DSCAML1, NGEF (neuronal guanine nucleotide exchange factor), MARC1, GPRASP1, RAB26, DEPTOR (DEP domain containing MTOR interacting protein), HMGCS2, EEPD1, CAMKK1, PDE1A, PPP1R3C, WDR88, SERF1A, KLHL32, SMTNL2, RASL11B, ABLIM1, TOX2, LMCD1, TMCC2 and CERK (ceramide kinase) may play key roles in the action mechanism of SARS-CoV-2 infection.
The construction of target genes - miRNA regulatory network and target genes - TF regulatory network analysis for up and down regulated genes, has been proven to be useful in the analysis of target genes involved in SARS-CoV-2 infection. Target genes such as CD7 [178] and ELOVL7 [179] were liable for advancement of HIV infection, but these genes may be associated with progression of SARS-CoV-2 infection. In general, our findings suggested that novel biomarkers such as SOD2, APOL6, NPR1, NTNG2, VAV3, ZNF703, FAXC (failed axon connections homolog, metaxin like GST domain), GPR137C, ZNF704, ABCA17P, REEP1 and TRAM1L1 may play key roles in the action mechanism of SARS-CoV-2 infection.
In conclusion, we conducted a comprehensive bioinformatics analysis on microarray data of SARS-CoV-2 infection. Pivotal DEGs (up and down regulated genes) and pathways were diagnosed and screened to provide a theoretical basis for potential drug target discovery and the molecular pathogensis of SARS-CoV-2 infection. 10 hub genes, especially CIITA, HSPA6, MYD88, SOCS3, TNFRSF10A, ADH1A, CACNA2D2, DUSP9, FMO5 and PDE1A, were found to differentiate remdesivir traded SARS-CoV-2 infection from non treated SARS-CoV-2 infection. Nevertheless, additional relevant investigation are needed to further confirm the identified up and down regulated genes, and pathways in SARS-CoV-2 infection.