Swine acute diarrhea syndrome coronavirus (SADS-CoV), a newly discovered enteric coronavirus, is the aetiological agent that causes severe clinical diarrhea and intestinal pathological damage in piglets. To understand the effect of SADS-CoV on host cells, we characterized the apoptotic pathways and elucidated mechanisms underlying the process of apoptotic cell death after SADS-CoV infection. SADS-CoV-infected cells showed evidence of apoptosis in vitro and in vivo. The use of a pan-caspase inhibitor resulted in the inhibition of SADS-CoV-induced apoptosis and reduction in SADS-CoV replication, suggestive of the association of a caspase-dependent pathway. Furthermore, SADS-CoV infection activated the initiators caspase-8 and -9 and upregulated FasL and Bid cleavage, demonstrating a crosstalk between the extrinsic and intrinsic pathways. However, the proapoptotic proteins Bax and Cytochrome c (Cyt c) relocalized to the mitochondria and cytoplasm, respectively, after infection by SADS-CoV. Moreover, Vero E6 and IPI-2I cells treated with cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPTP) opening, were completely protected from SADS-CoV-induced apoptosis and viral replication, suggesting the involvement of cyclophilin D (CypD) in these processes. Altogether, our results indicate that caspase-dependent FasL (extrinsic)- and mitochondria (intrinsic)- mediated apoptotic pathways play a central role in SADS-CoV-induced apoptosis that facilitates viral replication. In summary, these findings demonstrate mechanisms by which SADS-CoV induces apoptosis and improve our understanding of SADS-CoV pathogenesis.

中文翻译：

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猪急性腹泻综合征冠状病毒诱导的细胞凋亡是半胱天冬酶和亲环蛋白 D 依赖性的。


猪急性腹泻综合征冠状病毒（SADS-CoV）是一种新发现的肠道冠状病毒，是引起仔猪严重临床腹泻和肠道病理损害的病原。为了了解 SADS-CoV 对宿主细胞的影响，我们描述了 SADS-CoV 感染后细胞凋亡途径并阐明了细胞凋亡过程的潜在机制。 SADS-CoV 感染的细胞在体外和体内均显示出细胞凋亡的证据。使用泛半胱天冬酶抑制剂可抑制 SADS-CoV 诱导的细胞凋亡并减少 SADS-CoV 复制，这表明存在半胱天冬酶依赖性途径的关联。此外，SADS-CoV 感染激活了起始子 caspase-8 和 -9，并上调了 FasL 和 Bid 裂解，证明了外在途径和内在途径之间存在串扰。然而，在 SADS-CoV 感染后，促凋亡蛋白 Bax 和细胞色素 c (Cyt c) 分别重新定位到线粒体和细胞质。此外，用环孢素 A (CsA)（一种线粒体通透性转换孔 (MPTP) 开放抑制剂）处理的 Vero E6 和 IPI-2I 细胞完全免受 SADS-CoV 诱导的细胞凋亡和病毒复制的影响，这表明亲环蛋白 D 的参与。 CypD）在这些过程中。总而言之，我们的结果表明，半胱天冬酶依赖性 FasL（外在）和线粒体（内在）介导的细胞凋亡途径在 SADS-CoV 诱导的细胞凋亡中发挥着核心作用，从而促进病毒复制。总之，这些发现证明了 SADS-CoV 诱导细胞凋亡的机制，并提高了我们对 SADS-CoV 发病机制的理解。