Dipeptidyl peptidase 4 is a cofactor for porcine epidemic diarrhea virus infection

Porcine epidemic diarrhea virus (PEDV) is a member of the genus Alphacoronavirus in the family Coronaviridae, which has a mortality rate of up to 100 % in neonatal piglets and causes huge economic losses to the pig industry. The target cells of PEDV infection are porcine small intestinal epithelial cells, and the mechanism of PEDV invasion remains unclear. Our study found that dipeptidyl peptidase 4 (DPP4) acts as a cofactor for PEDV infection by promoting PEDV invasion and replication. Firstly, we mapped the expression profile of DPP4 in different tissues of 7-day-old piglets and found that DPP4 was highly expressed in the liver, lung, kidney, duodenum, jejunum, and ileum tissues of piglets. In addition, the immunohistochemical results showed that DPP4 was mainly distributed at the apical of intestinal villous epithelial cells in the jejunum of piglets. Further studies revealed that DPP4 expression was significantly lower in PEDV-infected porcine jejunal tissues and IPEC-J2 cells than in uninfected controls. PEDV invasion and replication could be inhibited by DPP4 inhibitor and specific antibody. Moreover, DPP4 knockout was able to significantly inhibit PEDV infection. Then, we found that endogenous DPP4 interacted with PEDV, and that preincubation of PEDV with endogenous DPP4 reduced viral infection. Finally, we predicted the docking of DPP4 and PEDV-S1-RBD proteins in silico, showing a strong binding tendency. Taken together, our study supports the hypothesis that DPP4 is a cofactor for PEDV infection.