Coxsackievirus B3 Replication Is Reduced by Inhibition of the Extracellular Signal-Regulated Kinase (ERK) Signaling Pathway

Abstract

Coxsackievirus B3 (CVB3) is the most common human pathogen for viral myocarditis. We have previously shown that the signaling protein p21ras GTPase-activating protein (RasGAP) is cleaved and that mitogenactivated protein kinases (MAPKs) ERK1/2 are activated in the late phase of CVB3 infection. However, the role of intracellular signaling pathways in CVB3-mediated myocarditis and the relative advantages of such pathways to host or virus remain largely unclear. In this study we extended our prior studies by examining the interaction between CVB3 replication and intracellular signaling pathways in HeLa cells. We observed that CVB3 infection induced a biphasic activation of ERK1/2, early transient activation versus late sustained activation, which were regulated by different mechanisms. Infection by UV-irradiated, inactivated virus capable of receptor binding and endocytosis triggered early ERK1/2 activation, but was insufficient to trigger late ERK1/2 activation. By using a general caspase inhibitor (zVAD.fmk) we further demonstrated that late ERK1/2 activation was not a result of CVB3-mediated caspase cleavage. Treatment of cells with U0126, a selective inhibitor of MAPK kinase (MEK), significantly inhibited CVB3 progeny release and decreased virus protein production. Furthermore, inhibition of ERK1/2 activation circumvented CVB3-induced apoptosis and viral protease-mediated RasGAP cleavage. Taken together, these data suggest that ERK1/2 activation is important for CVB3 replication and contributes to virus-mediated changes in host cells. Our findings demonstrate coxsackievirus takeover of a particular host signaling mechanism and uncover a prospective approach to stymie virus spread and preserve myocardial integrity.

Coxsackievirus Targets Proliferating Neuronal Progenitor Cells in the Neonatal CNS

“…Recent studies from several laboratories, including our own, indicate that cellular activation and proliferation may be required for productive coxsackievirus infection in tissue culture cells (Feuer et al, 2002;Luo et al, 2002), and viral binding to target cells has been found to stimulate cellular activation via the ERK1/2 (extracellular signal-regulated kinase) pathway (presumably through receptor signaling), which may in turn provide a better cellular setting for viral replication (Luo et al, 2002). In vivo studies correlate with these findings.…”

Characterization of pharmacologically active compounds that inhibit poliovirus and enterovirus 71 infectivity

“…For the replication process, membrane rearrangement utilizing ADP ribosylation factors (Arfs) and guanine nucleotide exchange factors (GEFs) (GBF1, BIG1/2) are required via direct and indirect interaction with viral 3A and 3CD proteins in coxsackievirus B3 (CVB3) and PV infections (Belov et al, 2007;Wessels et al, 2006). Cellular signalling via extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K) and stress-activated protein kinases (SAPKs) affected replication and/or the release of progeny virus in CVB3 infection by an unknown mechanism (Esfandiarei et al, 2004;Luo et al, 2002;Si et al, 2005).…”

Cellular kinase inhibitors that suppress enterovirus replication have a conserved target in viral protein 3A similar to that of enviroxime

“…In contrast, treatment with an inhibitor for PI3K significantly reduced viral RNA synthesis and release of progeny viruses in CVB3 infection (Esfandiarei et al, 2004). In CVB3 infection, a MEK1/2 inhibitor reduced viral protein synthesis and progeny virus release (Luo et al, 2002). Therefore, the MEK/ERK and PI3K/Akt signalling pathways might affect enterovirus infection in different ways depending on the virus species, but seemed to have little effect on PV and EV71 replication, at least by themselves.…”