Porcine reproductive and respiratory syndrome virus replication is suppressed by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway

Viruses are known to develop the ability to manipulate a variety of host cell signal transduction pathways in order to facilitate successful virus survival. However, to date, little is known about the intracellular signaling mechanisms involved in porcine reproductive and respiratory syndrome virus (PRRSV) replication. The extracellular signal-regulated kinase (ERK) pathway that transduces signals to modulate a wide range of cellular functions has been shown to regulate a number of viral infections. The present study therefore aimed to determine the role of this pathway during PRRSV infection in porcine alveolar macrophages. We found that the PRRSV infection induces early robust but transient activation of ERK1/2 by 6 h postinfection and thereafter the progressive decrease of its phosphorylation. However, the maximal induction of phosphorylated ERK1/2 seen at 6 h postinfection was inconsistent with synthesis of a viral nucleocapsid protein that was first evident by 12 h postinfection. These results indicate that ERK1/2 activation is mediated independently of viral gene expression during PRRSV replication. Notably, infection with UV-irradiated, inactivated virus, which is capable of receptor binding and internalization but prevents viral gene synthesis, was sufficient to trigger ERK1/2 phosphorylation, suggesting that the viral entry process may be responsible for early ERK activation. Treatment of cells with U0126, a selective ERK1/2 inhibitor, markedly diminished PRRSV infection and its inhibitory effect on PRRSV replication was exerted at the early stage in virus infection. Furthermore, inhibition of ERK activation resulted in significant suppression of subgenomic RNA transcription, viral protein translation, and progeny virus production. Taken together, the findings in this study suggest that the ERK signaling pathway plays an important role in postentry steps of the PRRSV replication cycle and beneficially contributes to viral infection. (C) 2010 Elsevier B.V. All rights reserved.