Porcine epidemic diarrhea virus induces caspase-independent apoptosis through activation of mitochondrial apoptosis-inducing factor

The present study sought to investigate whether porcine epidemic diarrhea virus (PEDV) induces apoptosis and to elucidate the mechanisms associated with apoptotic cell death after PEDV infection. PEDV-infected cells showed evidence of apoptosis in vitro and in vivo. However, experimental data indicated that the caspase cascade is not involved in PEDV-induced apoptotic cell death. Interestingly, mitochondrial apoptosis-inducing factor (AIF) was found to translocate to the nucleus during PEDV infection, and AIF relocalization was completely abrogated by the presence of cyclosporin A (CsA), an inhibitor of cyclophilin D (CypD) that is an essential component of the mitochondrial permeabilization transition pore (mPTP) complex. CsA treatment resulted in significant inhibition of PEDV-triggered apoptosis and suppressed PEDV replication. Furthermore, direct inhibition of AIF strongly impaired PEDV infection and virus-induced apoptosis. Altogether, our results indicate that a caspase-independent mitochondrial AIF-mediated pathway plays a central role in PEDV-induced apoptosis to facilitate viral replication and pathogenesis.
Highlights • PEDV induced apoptotic cell death in vitro and in vivo. • Inhibition of caspase activation did not affect apoptosis or PEDV infection. • Mitochondrial AIF translocated to the nucleus during the course of PEDV infection. • Treatment of CypD or AIF inhibitor strongly impaired apoptosis and PEDV replication. • PEDV-induced apoptosis is mitochondrial AIF dependent and caspase dispensable.