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Role of intestinal extracellular matrix-related signaling in porcine epidemic diarrhea virus infection.

ABSTRACT: Porcine epidemic diarrhea virus (PEDV) is emerging as a major threat to the global swine industry. Clinical PEDV infection is associated with severe intestinal lesions, resulting in absorptive dysfunction and high mortality rates in suckling piglets. The extracellular matrix (ECM) is an important component of intestinal tissue, providing a structural framework and conveying tissue-specific signals to nearby enterocytes. In this study, we investigated the extensive ECM remodeling observed in intestinal epithelial cells infected with PEDV and elucidated the associated activated ECM receptor-related pathways. Protein-protein interaction network analysis revealed two significantly differentially expressed genes (cluster of differentiation 44 [CD44] and serpin family E member 1 [SERPINE1]) associated with the ECM. At the transcriptional level, both genes exhibited significant positive correlation with the extent of PEDV replication. Similarly, the expression of CD44 and PAI-1 (encoded by SERPINE1) was also increased in the intestines of piglets during viral infection. Furthermore, CD44 exhibited antiviral activity by enhancing the expression of antiviral cytokines (e.g., interleukin [IL]-6, IL-18, IL-11, and antimicrobial peptide beta-defensin 1) by activating nuclear factor-κB signaling. Conversely, PAI-1 was found to promote the release of progeny virions during PEDV infection, despite a decreased intracellular viral load. Nevertheless, the underlying mechanisms are still unclear. Taken together, our results highlighted the biological roles of specific ECM-regulated genes, i.e., CD44 and SERPINE1 in suppressing and promoting PEDV infection, thereby providing a theoretical foundation for the role of the ECM in intestinal infections and identifying potential therapeutic targets for PEDV.

SUBMITTER: Li Y

PROVIDER: S-EPMC8451458 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Porcine epidemic diarrhea virus (PEDV), a member of the group of alphacoronaviruses, is the pathogen of a highly contagious gastrointestinal swine disease. The elucidation of the events associated with the intestinal epithelial response to PEDV infection has been limited by the absence of good in vitro porcine intestinal models that recapitulate the multicellular complexity of the gastrointestinal tract. Here, we generated swine enteroids from the intestinal crypt stem cells of the duodenum, jejunum, or ileum and found that the generated enteroids are able to satisfactorily recapitulate the complicated intestinal epithelium in vivo and are susceptible to infection by PEDV. PEDV infected multiple types of cells, including enterocytes, stem cells, and goblet cells, and exhibited segmental infection discrepancies compared with ileal enteroids and colonoids, and this finding was verified in vivo Moreover, the clinical isolate PEDV-JMS propagated better in ileal enteroids than the cell-adapted isolate PEDV-CV777, and PEDV infection suppressed interferon (IFN) production early during the infection course. IFN lambda elicited a potent antiviral response and inhibited PEDV in enteroids more efficiently than IFN alpha (IFN-?). Therefore, swine enteroids provide a novel in vitro model for exploring the pathogenesis of PEDV and for the in vitro study of the interplay between a host and a variety of swine enteric viruses.IMPORTANCE PEDV is a highly contagious enteric coronavirus that causes significant economic losses, and the lack of a good in vitro model system is a major roadblock to an in-depth understanding of PEDV pathogenesis. Here, we generated a porcine intestinal enteroid model for PEDV infection. Utilizing porcine intestinal enteroids, we demonstrated that PEDV infects multiple lineages of the intestinal epithelium and preferably infects ileal enteroids over colonoids and that enteroids prefer to respond to IFN lambda 1 over IFN-?. These events recapitulate the events that occur in vivo This study constitutes the first use of a primary intestinal enteroid model to investigate the susceptibility of porcine enteroids to PEDV and to determine the antiviral response following infection. Our study provides important insights into the events associated with PEDV infection of the porcine intestine and provides a valuable in vitro model for studying not only PEDV but also other swine enteric viruses.

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Role of intestinal extracellular matrix-related signaling in porcine epidemic diarrhea virus infection.

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