Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Lines and Virus Infection
2.2. Selection of GEO and EMBL-EBI Data
2.3. Differential Expression Analysis
2.4. Over-Representation Analysis
2.5. Transcription Factor Enrichment Analysis (TFEA)
2.6. Code Availability
3. Results
3.1. Samples Across Datasets Showed Divergence Due to Tissue Origin of the HIEs Line and Viral Infection
3.2. Most Non-Weakly Expressed Genes are Shared Across Datasets Including a Number of Innate Immune Response Genes
3.3. Differential Expression Analysis Showed That HIE Responses Against Astrovirus, Norovirus and Rotavirus Is Primarily Characterized by an Up-Regulation of Interferon-Stimulated Genes (ISGs)
3.4. Antiviral Defense and IFN Signaling Represent a Conserved Response of the Epithelium to Viral Infection
3.5. Distinct DEGs and Biological Processes (BP) were Also Noted for Each Enteric Virus
3.6. Transcription Factor Enrichment Analysis (TFEA) Revealed That the Conserved Intestinal Epithelial Response against the Three Enteric Viruses is Driven by STAT1/STAT2, IRF1, and NFkB
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Differential Expression Analysis Summary | |||||
---|---|---|---|---|---|
Dataset | HIEs | # Genes Analyzed | DEGs | Up-Regulated-DEGs | Down-Regulated DEGs |
astrovirus-infected | duodenal | 11,824 | 42 | 42 | 0 |
norovirus-infected | ileal | 12,917 | 109 | 109 | 0 |
rotavirus-infected | jejunal | 12,416 | 75 | 71 | 4 |
Shared Differentially Expressed Genes (DEGs) and IFN Responses | ||||||
---|---|---|---|---|---|---|
HGNC Symbol | Ensemble Gene ID | Entrez Gene ID | Entrez Gene Description | Type I IFN | Type II IFN | Type III IFN |
BATF2 | ENSG00000168062 | 116071 | basic leucine zipper ATF-like transcription factor 2 | yes | yes | yes |
CMPK2 | ENSG00000134326 | 129607 | cytidine/uridine monophosphate kinase 2 | yes | yes | no |
CXCL10 | ENSG00000169245 | 3627 | C-X-C motif chemokine ligand 10 | yes | yes | no |
DDX58 | ENSG00000107201 | 23586 | DExD/H-box helicase 58 | yes | yes | yes |
DDX60 | ENSG00000137628 | 55601 | DExD/H-box helicase 60 | yes | yes | no |
DHX58 | ENSG00000108771 | 79132 | DExH-box helicase 58 | yes | yes | no |
EPSTI1 | ENSG00000133106 | 94240 | epithelial stromal interaction 1 | yes | yes | yes |
HELZ2 | ENSG00000130589 | 85441 | helicase with zinc finger 2 | yes | yes | yes |
HERC5 | ENSG00000138646 | 51191 | HECT and RLD domain containing E3 ubiquitin protein ligase 5 | yes | yes | no |
HSH2D | ENSG00000196684 | 84941 | hematopoietic SH2 domain containing | yes | yes | no |
IFI16 | ENSG00000163565 | 3428 | interferon gamma inducible protein 16 | yes | yes | no |
IFIH1 | ENSG00000115267 | 64135 | interferon induced with helicase C domain 1 | yes | yes | yes |
IFIT1 | ENSG00000185745 | 3434 | interferon induced protein with tetratricopeptide repeats 1 | yes | yes | yes |
IFIT2 | ENSG00000119922 | 3433 | interferon induced protein with tetratricopeptide repeats 2 | yes | yes | yes |
IFIT3 | ENSG00000119917 | 3437 | interferon induced protein with tetratricopeptide repeats 3 | yes | yes | yes |
IFITM1 | ENSG00000185885 | 8519 | interferon induced transmembrane protein 1 | yes | yes | no |
ISG15 | ENSG00000187608 | 9636 | ISG15 ubiquitin like modifier | yes | yes | yes |
LAMP3 | ENSG00000078081 | 27074 | lysosomal associated membrane protein 3 | yes | yes | no |
LAP3 | ENSG00000002549 | 51056 | leucine aminopeptidase 3 | yes | yes | no |
MX1 | ENSG00000157601 | 4599 | MX dynamin like GTPase 1 | yes | yes | yes |
MX2 | ENSG00000183486 | 4600 | MX dynamin like GTPase 2 | yes | yes | no |
OAS2 | ENSG00000111335 | 4939 | 2′-5′-oligoadenylate synthetase 2 | yes | yes | no |
OAS3 | ENSG00000111331 | 4940 | 2′-5′-oligoadenylate synthetase 3 | yes | yes | yes |
OASL | ENSG00000135114 | 8638 | 2′-5′-oligoadenylate synthetase like | yes | yes | yes |
PARP10 | ENSG00000178685 | 84875 | poly(ADP-ribose) polymerase family member 10 | yes | yes | yes |
RSAD2 | ENSG00000134321 | 91543 | radical S-adenosyl methionine domain containing 2 | yes | yes | no |
SAMHD1 | ENSG00000101347 | 25939 | SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 | yes | yes | no |
STAT1 | ENSG00000115415 | 6772 | signal transducer and activator of transcription 1 | yes | yes | yes |
STAT2 | ENSG00000170581 | 6773 | signal transducer and activator of transcription 2 | yes | yes | yes |
USP18 | ENSG00000184979 | 11274 | ubiquitin specific peptidase 18 | yes | yes | yes |
XAF1 | ENSG00000132530 | 54739 | XIAP associated factor 1 | yes | yes | no |
ZBP1 | ENSG00000124256 | 81030 | Z-DNA binding protein 1 | yes | yes | no |
Gene Ontology (GO) Over-Representation Analysis Summary | ||||
---|---|---|---|---|
Dataset | HIE | # DEGs | # DEGs Assigned to BP Categories | # BP Categories Over-Represented |
astrovirus-infected | duodenal | 42 | 41 | 18 |
norovirus-infected | ileal | 109 | 103 | 26 |
rotavirus-infected | jejunal | 75 | 69 | 23 |
Uniquely Over-Represented Biological Processes (BPs) for each Dataset Analyzed | |||||||
---|---|---|---|---|---|---|---|
Dataset | HIEs | GO Term ID | GO Term Description | Gene Ratio | Gene Count | adj. p-Value | Gene ID |
astrovirus-infected | duodenal | GO:0050688 | regulation of defense response to virus | 0.12 | 5 | 0.00012 | IFIT1,HERC5,DDX60,DHX58,STAT1 |
norovirus-infected | ileal | GO:1903900 | regulation of viral life cycle | 0.27 | 28 | 0.00000 | OAS2,OASL,RSAD2,ISG15,LAMP3,OAS3,IFITM3,IFIT1,MX1, IFITM1,BST2,OAS1,IFI16,LGALS9,TRIM22,PARP10,EIF2AK2, TRIM5,SHFL,PLSCR1,IFIT5,APOBEC3F,ZC3HAV1,ADAR, TRIM34,TRIM25,TRIM14,TRIM21 |
norovirus-infected | ileal | GO:0019058 | viral life cycle | 0.27 | 28 | 0.00000 | OAS2,OASL,RSAD2,ISG15,LAMP3,OAS3,IFITM3,IFIT1,MX1, IFITM1,BST2,OAS1,IFI16,LGALS9,TRIM22,PARP10,EIF2AK2, TRIM5,SHFL,PLSCR1,IFIT5,APOBEC3F,ZC3HAV1,ADAR, TRIM34,TRIM25,TRIM14,TRIM21 |
norovirus-infected | ileal | GO:0034340 | response to type I interferon | 0.26 | 27 | 0.00000 | OAS2,OASL,RSAD2,ISG15,OAS3,USP18,IFIT3,IFITM3,XAF1, IFIT1,MX1,MX2,IFITM1,ZBP1,BST2,IFIT2,OAS1,STAT1,IFI35, SHFL,IRF9,SP100,ADAR,STAT2,SAMHD1,TRIM56,PSMB8 |
norovirus-infected | ileal | GO:0000209 | protein polyubiquitination | 0.15 | 15 | 0.00000 | HERC5,UBE2L6,HERC6,TRIM22,PARP10,TRIM5,DTX3L,NMI, RNF213,TRIM34,PSMB9,TRIM14,TRIM21,TRIM56,PSMB8 |
norovirus-infected | ileal | GO:0002683 | negative regulation of immune system process | 0.12 | 12 | 0.00020 | CD274,BST2,GBP1,IFI16,DHX58,LGALS9,SOCS1,PARP14,NMI, ADAR,SAMHD1,TLR3 |
norovirus-infected | ileal | GO:0051701 | interaction with host | 0.11 | 11 | 0.00002 | IFITM3,IFIT1,IFITM1,LGALS9,TRIM22,EIF2AK2,TRIM5,TRIM34, TRIM25,TRIM14,TRIM21 |
norovirus-infected | ileal | GO:0043123 | positive regulation of I-kappaB kinase/NF-kappaB signaling | 0.10 | 10 | 0.00006 | BST2,LGALS9,TRIM22,TRIM5,IFIT5,TRIM34,TRIM25,TLR3, TRIM14,TRIM21 |
norovirus-infected | ileal | GO:0046718 | viral entry into host cell | 0.09 | 9 | 0.00001 | IFITM3,IFITM1,LGALS9,TRIM22,TRIM5,TRIM34,TRIM25, TRIM14,TRIM21 |
norovirus-infected | ileal | GO:0051092 | positive regulation of NF-kappaB transcription factor activity | 0.09 | 9 | 0.00007 | LGALS9,TRIM22,EIF2AK2,TRIM5,TRIM34,TRIM25,TLR3, TRIM14,TRIM21 |
norovirus-infected | ileal | GO:0071360 | cellular response to exogenous dsRNA | 0.04 | 4 | 0.00029 | IFIT1,DDX58,IFIH1,TLR3 |
rotavirus-infected | jejunal | GO:0048525 | negative regulation of viral process | 0.25 | 17 | 0.00000 | IFNL3,IFIT1,OAS2,RSAD2,ISG15,CCL5,MX1,IFITM1,IFI16, OASL,IFITM3,OAS3,STAT1,EIF2AK2,ZC3HAV1,TRIM5,PLSCR1 |
rotavirus-infected | jejunal | GO:0050778 | positive regulation of immune response | 0.23 | 16 | 0.00000 | IFNL2,IFNL1,IFNL3,RSAD2,CCL5,DDX58,IFI16,CD274,ZBP1, PARP9,NLRC5,IRF7,GBP1,TREX1,TRIM5,PLSCR1 |
rotavirus-infected | jejunal | GO:0007259 | receptor signaling pathway via JAK-STAT | 0.10 | 7 | 0.00002 | IFNL2,IFNL1,IFNL3,CCL5,PARP9,STAT1,STAT2 |
rotavirus-infected | jejunal | GO:0002753 | cytoplasmic pattern recognition receptor signaling pathway | 0.07 | 5 | 0.00110 | DDX58,IFIH1,DDX60,DHX58,IRF7 |
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Cieza, R.J.; Golob, J.L.; Colacino, J.A.; Wobus, C.E. Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses. Viruses 2021, 13, 1059. https://doi.org/10.3390/v13061059
Cieza RJ, Golob JL, Colacino JA, Wobus CE. Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses. Viruses. 2021; 13(6):1059. https://doi.org/10.3390/v13061059
Chicago/Turabian StyleCieza, Roberto J., Jonathan L. Golob, Justin A. Colacino, and Christiane E. Wobus. 2021. "Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses" Viruses 13, no. 6: 1059. https://doi.org/10.3390/v13061059
APA StyleCieza, R. J., Golob, J. L., Colacino, J. A., & Wobus, C. E. (2021). Comparative Analysis of Public RNA-Sequencing Data from Human Intestinal Enteroid (HIEs) Infected with Enteric RNA Viruses Identifies Universal and Virus-Specific Epithelial Responses. Viruses, 13(6), 1059. https://doi.org/10.3390/v13061059