Swine acute diarrhea syndrome coronavirus-induced apoptosis is caspase- and cyclophilin D- dependent

• Published in: Emerging microbes & infections 2020-01, Vol.9 (1), p.439-456
• Main Authors: Zhang, Jiyu, Han, Yuru, Shi, Hongyan, Chen, Jianfei, Zhang, Xin, Wang, Xiaobo, Zhou, Ling, Liu, Jianbo, Zhang, Jialin, Ji, Zhaoyang, Jing, Zhaoyang, Ma, Jingyun, Shi, Da, Feng, Li
• Format: Article
• Language: English
• Subjects: Alphacoronavirus - physiology; Animals; Apoptosis; apoptosis-inducing factor; Caspases - metabolism; Chlorocebus aethiops; Coronavirus Infections - metabolism; Coronavirus Infections - virology; Coronaviruses; Diarrhea; Infections; pathogenesis; Peptidyl-Prolyl Isomerase F - genetics; Peptidyl-Prolyl Isomerase F - metabolism; SADS-CoV; Swine; Vero Cells; Virus Replication
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1080/22221751.2020.1722758

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.