Antiviral Potential of ERK/MAPK and PI3K/AKT/mTOR Signaling Modulation for Middle East Respiratory Syndrome Coronavirus Infection as Identified by Temporal Kinome Analysis
| Autor: | Brit J. Hart, Peter B. Jahrling, Britini L. Ork, Dawn Traynor, Julie Dyall, Jens H. Kuhn, Jason Kindrachuk, Gene G. Olinger, Steven Mazur, Lisa E. Hensley, Matthew B. Frieman, Reed F. Johnson, Michael R. Holbrook |
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| Rok vydání: | 2015 |
| Předmět: |
MAPK/ERK pathway
Blotting Western Enzyme-Linked Immunosorbent Assay Biology Antiviral Agents Cell Line Phosphatidylinositol 3-Kinases Humans Pharmacology (medical) Kinome Phosphorylation Extracellular Signal-Regulated MAP Kinases Protein kinase A Protein kinase B PI3K/AKT/mTOR pathway Pharmacology Kinase TOR Serine-Threonine Kinases Computational Biology Infectious Diseases Immunology Hepatocytes Middle East Respiratory Syndrome Coronavirus Cancer research Signal transduction Coronavirus Infections Signal Transduction |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.03659-14 |
| Popis: | Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus, and infections with this virus can result in acute respiratory syndrome with renal failure. Globally, MERS-CoV has been responsible for 877 laboratory-confirmed infections, including 317 deaths, since September 2012. As there is a paucity of information regarding the molecular pathogenesis associated with this virus or the identities of novel antiviral drug targets, we performed temporal kinome analysis on human hepatocytes infected with the Erasmus isolate of MERS-CoV with peptide kinome arrays. bioinformatics analysis of our kinome data, including pathway overrepresentation analysis (ORA) and functional network analysis, suggested that extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling responses were specifically modulated in response to MERS-CoV infection in vitro throughout the course of infection. The overrepresentation of specific intermediates within these pathways determined by pathway and functional network analysis of our kinome data correlated with similar patterns of phosphorylation determined through Western blot array analysis. In addition, analysis of the effects of specific kinase inhibitors on MERS-CoV infection in tissue culture models confirmed these cellular response observations. Further, we have demonstrated that a subset of licensed kinase inhibitors targeting the ERK/MAPK and PI3K/AKT/mTOR pathways significantly inhibited MERS-CoV replication in vitro whether they were added before or after viral infection. Taken together, our data suggest that ERK/MAPK and PI3K/AKT/mTOR signaling responses play important roles in MERS-CoV infection and may represent novel drug targets for therapeutic intervention strategies. |
| Databáze: | OpenAIRE |
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