Porcine epidemic diarrhea virus causes diarrhea by activating EGFR to regulates NHE3 activity and mobility on plasma membrane

Abstract

As part of the genus Enteropathogenic Coronaviruses, Porcine Epidemic Diarrhea Virus (PEDV) is an important cause of early diarrhea and death in piglets, and one of the most difficult swine diseases to prevent and control in the pig industry. Previously, we found that PEDV can block Na+ absorption and induce diarrhea in piglets by inhibiting the activity of the sodium-hydrogen ion transporter NHE3 in pig intestinal epithelial cells, but the mechanism needs to be further explored. The epidermal growth factor receptor (EGFR) has been proved to be one of the co-receptors involved in many viral infections and a key protein involved in the regulation of NHE3 activity in response to various pathological stimuli. Based on this, our study used porcine intestinal epithelial cells (IPEC-J2) as an infection model to investigate the role of EGFR in regulating NHE3 activity after PEDV infection. The results showed that EGFR mediated viral invasion by interacting with PEDV S1, and activated EGFR regulated the downstream EGFR/ERK signaling pathway, resulting in decreased expression of NHE3 and reduced NHE3 mobility at the plasma membrane, which ultimately led to decreased NHE3 activity. The low level of NHE3 expression in intestinal epithelial cells may be a key factor leading to PEDV-induced diarrhea in newborn piglets. This study reveals the importance of EGFR in the regulation of NHE3 activity by PEDV and provides new targets and clues for the prevention and treatment of PEDV-induced diarrhea in piglets.

Developing Next-Generation Live Attenuated Vaccines for Porcine Epidemic Diarrhea Using Reverse Genetic Techniques

“…In contrast, the binding of PEDV S1 to the DnaJ heat shock protein family (Hsp40) member A3 (DNAJA3) protein on the cell surface via its central part (aa 379-479) interferes with the attachment of PEDV to host cells [121]. In addition, during PEDV infection, the S1 subunit binds to the epidermal growth factor receptor (EGFR) and triggers the EGFR signaling pathway, ultimately inhibiting the activity of the sodium-hydrogen ion transporter, Na + /H + exchanger (NHE3) [52]. Mechanistically, during PEDV infection, the S1-EGFR-ERK (extracellular-signal-related kinase) signaling pathway is activated to reduce the expression and mobility of NHE3 on the cell surface, impairing Na + absorption by the intestine and resulting in diarrhea in piglets.…”