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.

摘要

猪流行性腹泻病毒 (PEDV) 正在成为全球养猪​​业的主要威胁。临床 PEDV 感染与严重的肠道损伤有关，导致哺乳仔猪的吸收功能障碍和高死亡率。细胞外基质 (ECM) 是肠组织的重要组成部分，提供结构框架并将组织特异性信号传递到附近的肠细胞。在这项研究中，我们研究了在感染 PEDV 的肠上皮细胞中观察到的广泛的 ECM 重塑，并阐明了相关的活化 ECM 受体相关途径。蛋白质-蛋白质相互作用网络分析揭示了两个显着差异表达的基因（分化簇 44 [ CD44 ] 和丝氨酸蛋白酶抑制剂家族 E 成员 1 [ SERPINE1]) 与 ECM 相关联。在转录水平，这两个基因都与PEDV复制的程度呈显着正相关。类似地，病毒感染期间仔猪肠道中 CD44 和 PAI-1（由SERPINE1编码）的表达也增加。此外，CD44 通过激活核因子-κB 信号传导增强抗病毒细胞因子（例如，白细胞介素 [IL]-6、IL-18、IL-11 和抗菌肽 β-防御素 1）的表达，从而表现出抗病毒活性。相反，尽管细胞内病毒载量降低，但发现 PAI-1 在 PEDV 感染期间促进子代病毒粒子的释放。然而，潜在的机制仍不清楚。总之，我们的结果突出了特定 ECM 调节基因的生物学作用，即CD44和SERPINE1在抑制和促进 PEDV 感染中的作用，从而为 ECM 在肠道感染中的作用和确定 PEDV 的潜在治疗靶点提供了理论基础。