Role of MAPK Signaling in the Pathogenesis of Influenza

Influenza A virus is a RNA virus belonging to the family Orthomyxoviridae. Its genome consists of eight single-stranded RNA segments of negative polarity that encodes up to 11 proteins. Upon viral infection, a number of intracellular signaling pathways are triggered in defense of the host cell as well as to facilitate viral functions. The MAPK (ERK, JNK and p38 MAPK) signaling pathways play an important role in virally infected cells.The ERK signaling pathway is mainly involved in the export of ribonucleoprotein (RNP) complexes from the nucleus. Influenza A viruses replicate within the nucleus of infected cells. Viral genomic RNA, three polymerase subunits (PB2, PB1 and PA) and the nucleoprotein(NP) form RNPs that are exported from the nucleus late during the infectious cycle. Studies show that enhanced viral polymerase activity promotes the replication and transcription of viral RNA leading to increased accumulation of HA on the cell surface. HA membrane accumulation and its tight association with lipid-raft domains triggers activation of the Ras/MEK/ERK cascade via PKCα activation and induces RNP export. Recent studies show that RABGEF1, a protein that physically interacts with Ras, binds influenza A virus proteins NP, PB1, PB2 and PA.JNK and p38 MAPK play a role in response to viral infection by inducing cytokines such as CCL5 (RANTES), CCL2 (MCP-1) and IFNs. JNK and p38 MAPK also play a role in the regulation of apoptosis in infected cells. The upstream kinase ASK-1 phosphorylates and activates MKK4/7 and MKK3/6 leading to the activation of JNK and p38 MAPK, respectively. These molecules in turn activate mediators of apoptosis such as caspase-3, BAX and Bcl-2. JNK has been found to bind the influenza A virus proteins NS1, NP, PB1, PB2 and PA.Studies show that MAPKs play a role in influenza virus induction of prostaglandin E2 from arachidonic acid in bronchial epithelial cells. Influenza A infection results in the phosphorylation of ERK, JNK and p38 MAPK. MAPK family members then increase the production of prostaglandin E2 either directly or via certain enzymes involved in its synthesis such as COX-2 and PLA2.