Porcine deltacoronavirus induces caspase-dependent apoptosis through activation of the cytochrome c-mediated intrinsic mitochondrial pathway

Abstract

Porcine deltacoronavirus (PDCoV), a newly discovered enteric coronavirus, is a causative agent of severe clinical diarrhea and intestinal pathological damage in piglets. As a first step toward understanding the effect of PDCoV on host cells, we elucidated mechanisms underlying the process of apoptotic cell death after PDCoV infection. The use of a pan-caspase inhibitor resulted in the inhibition of PDCoV-induced apoptosis and reduction of PDCoV replication, suggestive of the association of a caspase-dependent pathway. Furthermore, PDCoV infection necessitated the activation of the initiator caspase-9 responsible for the intrinsic mitochondrial apoptosis pathway. Experimental data indicated that PDCoV infection led to Bax-mediated mitochondrial outer membrane permeabilization (MOMP), resulting in specific relocation of the mitochondrial cytochrome c (cyt c) into the cytoplasm. Treatment with cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (MPTP) opening, significantly suppressed PDCoV-triggered apoptosis and viral replication. Moreover, cyt c release was completely abrogated in PDCoV-infected cells in the presence of CsA, suggesting the critical role of MPTP in intrinsic apoptosis in response to PDCoV infection. Altogether, our results indicate that PDCoV infection stimulates MOMP either via Bax recruitment or MPTP opening to permit the release of apoptogenic cyt c into the cytoplasm, thereby leading to execution of the caspase-dependent intrinsic apoptosis pathway to facilitate viral replication in vitro.

Porcine deltacoronavirus (PDCoV) modulates calcium influx to favor viral replication

“…Apart from its pivotal roles in virus entry and replication, virusinduced Ca 2+ oscillation also regulates other biological processes, such as ER stress, apoptosis and autophagy. Previous studies suggested that PDCoV infection induces apoptosis in swine testicular and LLC-PK1 cells, possibly through the activation of the cytochrome c-mediated intrinsic mitochondrial pathway (Jung et al, 2016;Lee and Lee, 2018). A recent study also showed that PDCoV infection induces autophagosome-like vesicles associated with increased autophagic activity (Qin et al, 2019).…”

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

“…When PARP cleavage in SADS-CoV-infected cells was blocked, SADS-CoV infection was dramatically inhibited. These findings suggested that apoptosis is required for the replication of SADS-CoV as shown in PDCoV [12]. Thus, the caspase-dependent apoptotic pathway seems to be manipulated by SADS-CoV to ensure competent viral replication in target cells.…”

“…However, some viruses induce apoptosis to facilitate the release and dissemination of viral progeny for further invasion, which are important biological activities in viral pathogenesis and disease processes that promote cell death and tissue injury. Recent studies have demonstrated the ability of numerous coronaviruses to elicit or inhibit apoptosis either directly or indirectly during their replication cycles such as transmissible gastroenteritis virus (TGEV) [10,35], avian infectious bronchitis virus (IBV) [36], mouse hepatitis virus (MHV) [37], porcine deltacoronavirus (PDCoV) [12], and porcine epidemic diarrhea virus (PEDV) [11]. Although various viruses are known to modulate apoptosis as a critical armament to complete their replication cycle, whether SADS-CoV induces apoptosis remains unclear.…”

“…Apoptosis also represents an important antivirus defense mechanism of host cells, and viruses have evolved various sophisticated strategies to manipulate host cells such as limit anti-virus responses of the host, which may be advantageous for viral replication and persistent infection [5]. In recent years, many viruses from different families, including some coronaviruses, have been found to induce apoptosis during their infection cycles [8][9][10][11][12].…”

Lactobacillus acidophilus S-layer protein-mediated inhibition of PEDV-induced apoptosis of Vero cells

“…Caspase-8 is an initiator caspase, with the released active dimer known to cleave a variety of downstream targets, including the executioner caspase, caspase-3 (Keller et al, 2018). Caspase-3 is activated by both extrinsic and intrinsic apoptotic pathways, and is responsible for the morphological features of apoptosis (Lee and Lee, 2018). Apoptotic factors caspase-3 and caspase-8 are up-regulated during PEDV infection, especially in the later stages (Ming-Ming et al, 2014).…”