Porcine deltacoronavirus (PDCoV) is an emerging infectious disease of swine with unknown zoonotic potential. Phylogenetic analysis suggests that PDCoV originated 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 infects or causes morbidity in humans. Currently, there are no treatments or vaccines available for PDCoV,partially due to the unknown mechanisms of infection.In this study, we comparethegene expression profiles of an established host, swinecells, to a potential emerging host, human cells, after infection with PDCoV. Cell lines derived from intestinal lineages were used 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. On the transcriptional level, the novelhost human cells exhibited a more robust response to PDCoV infection in comparison to the primary pig host cells, with more differentially expressed genes (DEGs) in humans, 7486, in comparison to pigs, 1134.Our research shows that key immune associated DEGs are shared between human and pig cells during PDCoV infection. These included genes related to the NF-kappa-B 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. MAP4K4 was unique in up-regulated DEGs in humans in the apoptosis signaling pathway. Our findings provide an important foundation that contributes to an understanding of the mechanisms of PDCoV infection control across different hosts. To our knowledge, this is the first report of transcriptome analysis of human cells infected by PDCoV.