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

• 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.

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.