An ERK-p38 subnetwork coordinates host cell apoptosis and necrosis during coxsackievirus B3 infection

Cell Host Microbe. 2013 Jan 16;13(1):67-76. doi: 10.1016/j.chom.2012.11.009. Epub 2013 Jan 16.


The host response to a virus is determined by intracellular signaling pathways that are modified during infection. These pathways converge as networks and produce interdependent phenotypes, making it difficult to link virus-induced signals and responses at a systems level. Coxsackievirus B3 (CVB3) infection induces death of cardiomyocytes, causing tissue damage and virus dissemination, through incompletely characterized host cell signaling networks. We built a statistical model that quantitatively predicts cardiomyocyte responses from time-dependent measurements of phosphorylation events modified by CVB3. Model analysis revealed that CVB3-stimulated cytotoxicity involves tight coupling between the host ERK and p38 MAPK pathways, which are generally thought to control distinct cellular responses. The kinase ERK5 requires p38 kinase activity and inhibits apoptosis caused by CVB3 infection. By contrast, p38 indirectly promotes apoptosis via ERK1/2 inhibition but directly causes CVB3-induced necrosis. Thus, the cellular events governing pathogenesis are revealed when virus-host programs are monitored systematically and deconvolved mathematically.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Coxsackievirus Infections / enzymology*
  • Coxsackievirus Infections / physiopathology*
  • Coxsackievirus Infections / virology
  • Enterovirus B, Human / genetics
  • Enterovirus B, Human / physiology*
  • Host-Pathogen Interactions
  • Humans
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mitogen-Activated Protein Kinase 7 / genetics
  • Mitogen-Activated Protein Kinase 7 / metabolism
  • Necrosis
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / metabolism*


  • MAPK1 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7
  • p38 Mitogen-Activated Protein Kinases