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Comparative Transcriptome Profiling of Human and Pig Intestinal Epithelial Cells After Comparative transcriptome profiling of human and pig intestinal epithelial cells after Deltacoronavirus infection Thesis Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Diana Cruz Pulido, MSc Graduate Program in Comparative and Veterinary Medicine. The Ohio State University 2020 Thesis Committee: Scott P. Kenney, PhD, Advisor Vanessa Hale, DVM, PhD Anastasia Vlasova, DVM, PhD Copyrighted by Diana Cruz Pulido 2020 Abstract Porcine deltacoronavirus (PDCoV) is an emerging global infectious disease of the swine industry with unknown potential to cause human disease. Phylogenetic analysis suggests that PDCoV originated relatively recently from a host-switching event between birds and mammals. Little is known about how PDCoV interacts with its differing hosts. Although human derived cell lines are susceptible to PDCoV infection, there is no direct evidence that PDCoV causes morbidity in humans. Currently, there are no treatments or vaccines available for PDCoV partially due to the mechanisms of infection remaining unknown. In this study, we explored the gene expression profiles of the primary host organism (swine) to a potential novel host (humans) after infection with PDCoV. For this we utilized cell lines derived from intestinal lineages to reproduce the primary sites of viral infection in the host. Porcine intestinal epithelial cells (IPEC-J2) and human intestinal epithelial cells (HIEC) were infected with PDCoV. At 24 h post infection, total cellular RNA was harvested and analyzed using RNA-sequencing (RNA-seq) technology. We found that there are more differentially expressed genes (DEGs) in humans, 7,486, in comparison to pigs, 1134. On the transcriptional level, humans as the naïve host appear to be showing a more aggressive response to PDCoV infection in comparison to the primary host, pigs. Our research shows key immune associated DEGs are shared between humans and pigs that were affected after PDCoV infection. These included genes related to the NF-kappa- β transcription factor family, the interferon (IFN) family, the protein kinase family, and signaling pathways such as the apoptosis signaling pathway, JAK-STAT signaling pathway, inflammation/cytokine – cytokine receptor signaling pathway, Toll-like ii receptor signaling pathway, NOD-like receptor signaling pathway, Ras signaling pathway and cytosolic DNA-sensing pathway. While similarities exist between humans and pigs in many pathways, our research suggests that adaptation of PDCoV to the porcine host required the ability to downregulate many response pathways including the interferon pathway and provides an important foundation that contributes to an understanding of the mechanisms of PDCoV infection across different hosts. This is the first report of transcriptome analysis of human cells infected by PDCoV. Keywords: PDCoV infection, RNA-seq technology, differentially expressed genes, pathways. iii Acknowledgments I would like to thank my advisor Dr. Scott Kenney for his enormous patience and support in implementing this idea/project in his lab; my committee members, Dr. Vanessa Hale and Dr. Anastasia Vlasova for their patience, guidance and valuable ideas in order to make the data analysis of this study stronger; my Bioinformatics specialist and dear husband, Dr. Wilber Ouma, for his patience and guidance in solving the most difficult bioinformatics tasks in this project; and Dr. Patricia Boley for her valuable support in the experimental part of this study that includes the implementation of RNA extraction and qRT-PCR. iv Vita September 2008 .............................................B.S. Microbiology, Universidad de los Andes. Bogota, Colombia. March 2010 ....................................................M.Sc. Biological Sciences. Universidad de los Andes. Bogota, Colombia. 2017 to present ..............................................Masters (PhD track) Student/ Graduate Research Associate. The Ohio State University - OARDC, Wooster, Ohio, USA Publications Cruz Diana P, Huertas Mónica G, Lozano Marcela, Zárate Lina and Zambrano María Mercedes. Comparative analysis of diguanylate cyclase and phosphodiesterase genes in Klebsiella pneumoniae. BMC Microbiology 2012, 12:139. Monica G. Huertas, Lina Zarate, Ivan C. Acosta, Leonardo Posada, Diana Cruz, Marcela Lozano and Maria M. Zambrano. Klebsiella pneumoniae yfiRNB operon affects biofilm formation, polysaccharide production and drug susceptibility. Microbiology 2014, 160. Fields of Study Major Field: Comparative and Veterinary Medicine. v Table of Contents Abstract ............................................................................................................................... ii Acknowledgments.............................................................................................................. iv Vita ...................................................................................................................................... v List of Tables .................................................................................................................... vii List of Figures .................................................................................................................. viii Chapter 1: Deltacoronavirus. Introduction ........................................................................ 1 1.1. Hypothesis and Objectives ..................................................................................... 12 Chapter 2: Transcriptome Analysis of IPEC and HIEC Cells in Response to Deltacoronavirus Infection ............................................................................................... 13 2.1. Materials and Methods ........................................................................................... 13 2.2. Results .................................................................................................................... 17 2.3. Discussion ........................................................................................................... 44 2.4. Conclusions ........................................................................................................ 51 References ......................................................................................................................... 55 Appendix A: IF Staining of the Inoculated IPEC cells ..................................................... 60 Appendix B: Common Upregulated and Downregulated DEGs in Humans and Pigs ..... 61 Appendix C: DEGs in humans and pigs in three Pathways .............................................. 62 vi List of Tables Table 1. RNA sequencing and Genome mapping results……………………………….33 Table 2. DEGs in H. sapiens (HIEC cells) and S. scrofa (IPEC cells) at 24 hpi vs no infected cells……………………………………………………………………………..33 Table 3. Gene Ontology classification of upregulated DEGs in humans and pigs at 24 hpi………………………………………………………………………………………..41 Table 4. Top 20 differential expressed genes in humans and pigs……………………...48 vii List of Figures Figure 1. Electrophoresis gel of 16 RNA samples (uninfected HIEC and IPEC cells)…19 Figure 2. Bioanalyzer electropherogram of the cDNA pooled library that contains twelve libraries of uninfected and infected HIEC and IPEC cells……………………..20 Figure 3. Quality control of reads in HIEC RNA-seq library (Hs_Dc_1) before trimming (A) and after trimming (B)………………………………………………………………22 Figure 4. Adapter removal in HIEC RNA-seq library (Hs_Dc_1) before trimming (A) and after trimming (B)…………………………………………………………………...23 Figure 5. The density distribution of log-CPM values before (A) and after (B) filtering low expressed genes in HIEC RNA-seq libraries……………………………………… 24 Figure 6. The density distribution of log-CPM values before (A) and after (B) filtering low expressed genes in IPEC RNA-seq libraries………………………………………...25 Figure 7. Box plots showing the distribution of log-cpm values for unnormalized (left panel) and normalized (right panel) data in HIEC RNA-seq libraries…………………..26 Figure 8. Box plots showing the distribution of log-cpm values for unnormalized (left panel) and normalized (right panel) data in IPEC RNA-seq libraries…………………...27 Figure 9. MDS plot based on biological coefficient of variation, and Histogram of the variances of the principal components of the Human Data set…………………………29 Figure 10. MDS plot based on biological coefficient of variation, and Histogram of the variances of the principal components of the Pig Data set……………………………..29 Figure 11. IF staining of the inoculated HIEC cells at 24 hpi………………………....31 viii Figure 12. DEGs in H. sapiens (HIEC cells)(A) and S. scrofa (IPEC cells) (B) at 24 hpi vs no infected cells………………………………………………………………………34 Figure 13. Heatmap of the top 100 genes that were differentially expressed in the PDCoV-infected HIEC cells (humans) (A) and the PDCoV-infected IPEC cells (pigs) (B) compared with the no infected cells……………………………………………………..35 Figure 14. KEGG Gene Set Enrichment Analysis of DEGs in humans (A) and pigs (B) at 24 hpi…………………………………………………………………………………..36 Figure 15. DEGs in 10 common immune response -associated pathways in pigs and humans after PDCoV infection…………………………………………………………..38 Figure 16. Common upregulated DEGs in humans at 24 hpi across 10 pathways……...39 Figure 17. Common upregulated DEGs in humans at 24 hpi across 10 pathways……. 40 Figure 18. Common upregulated DEGs in pigs at 24 hpi across 9 pathways…………..41 Figure 19. Common downregulated DEGs in humans at 24 hpi
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