Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for Middle East respiratory syndrome coronavirus infection as identified by temporal kinome analysis
JournalAntimicrobial Agents and Chemotherapy
PublisherAmerican Society for Microbiology
MetadataShow full item record
AbstractMiddle 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 signalregulated 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.
SponsorsNational Institutes of Health, NIH: R01AI095569
Keywordpeptide kinome arrays
Middle East Respiratory Syndrome Coronavirus
Extracellular Signal-Regulated MAP Kinases
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84921899175&doi=10.1128%2fAAC.03659-14&partnerID=40&md5=05146f5f76399af318f8368e6d8ab511; http://hdl.handle.net/10713/12407
- Cyclophilin inhibitors restrict Middle East respiratory syndrome coronavirus <i>via</i> interferon-λ <i>in vitro</i> and in mice.
- Authors: Sauerhering L, Kupke A, Meier L, Dietzel E, Hoppe J, Gruber AD, Gattenloehner S, Witte B, Fink L, Hofmann N, Zimmermann T, Goesmann A, Nist A, Stiewe T, Becker S, Herold S, Peteranderl C
- Issue date: 2020 Nov
- Electrostimulation during hindlimb unloading modulates PI3K-AKT downstream targets without preventing soleus atrophy and restores slow phenotype through ERK.
- Authors: Dupont E, Cieniewski-Bernard C, Bastide B, Stevens L
- Issue date: 2011 Feb
- A Yeast Suppressor Screen Used To Identify Mammalian SIRT1 as a Proviral Factor for Middle East Respiratory Syndrome Coronavirus Replication.
- Authors: Weston S, Matthews KL, Lent R, Vlk A, Haupt R, Kingsbury T, Frieman MB
- Issue date: 2019 Aug 15
- Abelson Kinase Inhibitors Are Potent Inhibitors of Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus Fusion.
- Authors: Coleman CM, Sisk JM, Mingo RM, Nelson EA, White JM, Frieman MB
- Issue date: 2016 Oct 1
- Middle East Respiratory Coronavirus Accessory Protein 4a Inhibits PKR-Mediated Antiviral Stress Responses.
- Authors: Rabouw HH, Langereis MA, Knaap RC, Dalebout TJ, Canton J, Sola I, Enjuanes L, Bredenbeek PJ, Kikkert M, de Groot RJ, van Kuppeveld FJ
- Issue date: 2016 Oct