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Respiratory Syncytial Virus Infection Results in Activation of Multiple Protein Kinase C Isoforms Leading to Activation of Mitogen-Activated Protein Kinase¹

Department of Medicine, University of Iowa College of Medicine and Veterans Administration Medical Center, Iowa City, IA 52242

Respiratory syncytial virus (RSV) is an important respiratory pathogen that preferentially infects epithelial cells in the airway and causes a local inflammatory response. Very little is known about the second messenger pathways involved in this response. To characterize some of the acute response pathways involved in RSV infection, we used cultured human epithelial cells (A549) and optimal tissue culture-infective doses (TCID₅₀) of RSV. We have previously shown that RSV-induced IL-8 release is linked to activation of the extracellular signal-related kinase (ERK) mitogen-activated protein kinase pathway. In this study, we evaluated the upstream events involved in ERK activation by RSV. RSV activated ERK at two time points, an early time point consistent with viral binding and a later sustained activation consistent with viral replication. We next evaluated the role of protein kinase C (PKC) isoforms in RSV-induced ERK kinase activity. We found that A549 cells contain the Ca²⁺-dependent isoforms and 1, and the Ca²⁺-independent isoforms , , , µ, , and . Western analysis showed that RSV caused no change in the amounts of these isoforms. However, kinase activity assays demonstrated activation of isoform within 10 min of infection, followed by a sustained activation of isoforms 1, , , and µ 24–48 h postinfection. A cell-permeable peptide inhibitor specific for the isoform decreased early ERK kinase activation by RSV. Down-regulation of the other PKC isoforms with PMA blocked the late sustained activation of ERK by RSV. These studies suggest that RSV activates multiple PKC isoforms with subsequent downstream activation of ERK kinase.

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