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

Virus Res. 2018 Jul 15:253:112-123. doi: 10.1016/j.virusres.2018.06.008. Epub 2018 Jun 22.

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.

Keywords: Apoptotic cell death; Caspase-dependent intrinsic pathway; Cytochrome c; MOMP; PDCoV.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspases / genetics
  • Caspases / metabolism*
  • Coronavirus / genetics
  • Coronavirus / physiology*
  • Coronavirus Infections / enzymology
  • Coronavirus Infections / physiopathology
  • Coronavirus Infections / veterinary*
  • Coronavirus Infections / virology
  • Cytochromes c / metabolism*
  • Mitochondria / metabolism*
  • Mitochondrial Membrane Transport Proteins / metabolism
  • Mitochondrial Permeability Transition Pore
  • Swine
  • Swine Diseases / enzymology
  • Swine Diseases / metabolism
  • Swine Diseases / physiopathology*
  • Swine Diseases / virology
  • Virus Replication

Substances

  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Permeability Transition Pore
  • Cytochromes c
  • Caspases