JNK and p38 mitogen-activated protein kinase pathways contribute to porcine epidemic diarrhea virus infection

Abstract

The mitogen-activated protein kinase (MAPK) pathways, which are central building blocks in the intracellular signaling network, are often manipulated by viruses of diverse families to favor their replication. Among the MAPK family, the extracellular signal-regulated kinase (ERK) pathway is known to be modulated during the infection with porcine epidemic diarrhea virus (PEDV); however, involvement of stress-activated protein kinases (SAPKs) comprising p38 MAPK and c-Jun NH2-terminal kinase (JNK) remains to be determined. Therefore, in the present study, we investigated whether activation of p38 MAPK and JNK cascades is required for PEDV replication. Our results showed that PEDV activates p38 MAPK and JNK1/2 up to 24h post-infection, whereas, thereafter their phosphorylation levels recede to baseline levels or even fall below them. Notably, UV-irradiated inactivated PEDV, which can enter cells but cannot replicate inside them, failed to induce phosphorylation of p38 MAPK and JNK1/2 suggesting that viral biosynthesis is essential for activation of these kinases. Treatment of cells with selective p38 or JNK inhibitors markedly impaired PEDV replication in a dose-dependent manner and these antiviral effects were found to be maximal during the early times of the infection. Furthermore, direct pharmacological inhibition of p38 MAPK or JNK1/2 activation resulted in a significant reduction of viral RNA synthesis, viral protein expression, and progeny release. However, independent treatments with either SAPK inhibitor did not inhibit PEDV-induced apoptotic cell death mediated by activation of mitochondrial apoptosis-inducing factor (AIF) suggesting that SAPKs are irrelevant to the apoptosis pathway during PEDV infection. In summary, our data demonstrated critical roles of the p38 and JNK1/2 signaling pathways in facilitating successful viral infection during the post-entry steps of the PEDV life cycle.

Porcine epidemic diarrhea virus infections induce apoptosis in Vero cells via a reactive oxygen species (ROS)/p53, but not p38 MAPK and SAPK/JNK signalling pathways

“…8A and B), indicating p38 MAPK and SAPK/JNK can be activated during PEDV infection. However, the ratio of Bax/Bcl-2 showed little change following inhibitor treatment, in agreement with previous studies (Lee et al, 2016). Taken together, these results clearly indicate that the PEDV dependent ROS/p53 mediated pathway induced apoptosis in Vero cells whereas p38 MAPK and SAPK/JNK were not involved in apoptosis.…”

Cellular cholesterol is required for porcine nidovirus infection

“…Lastly, cholesterol removal has been shown to result in the inhibition of cellular signaling pathways [53]. We previously found that PRRSV and PEDV activate specific intracellular signaling networks such as mitogen-activated protein kinase (MAPK) cascade pathways to favor replication of these viruses, but these signaling pathways are irrelevant to virus internalization [24,[28][29][30]. Based on these previous data, cellular cholesterol does not appear to act through MAPK signaling pathways.…”

PEDV and PDCoV Pathogenesis: The Interplay Between Host Innate Immune Responses and Porcine Enteric Coronaviruses

“…It is worth pointing out that the increase in serum proinflammatory cytokine and chemokine levels in both PEDV infected suckling and weaned pigs mentioned above could reflect the outcome of the simultaneous induction of the key components of the mitogen-activated protein kinase (MAPK) cascade including Erk1/2 and JNK/p38 (116,117), and the activation of NF-κB pathway (72,118) during the PEDV infection. As shown in the context of other pathogenic infections (119,120), the concurrent activation of both MAPK components and the transcription factor NF-κB during PEDV infection might lead to the upregulation of both pro-inflammatory cytokines and chemokines.…”