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

TitleAn ERK-p38 subnetwork coordinates host cell apoptosis and necrosis during coxsackievirus B3 infection.
Publication TypeJournal Article
Year of Publication2013
AuthorsJensen, KJ, Garmaroudi, FS, Zhang, J, Lin, J, Boroomand, S, Zhang, M, Luo, Z, Yang, D, Luo, H, McManus, BM, Janes, KA
JournalCell Host Microbe
Volume13
Issue1
Pagination67-76
Date Published2013 Jan 16
ISSN1934-6069
KeywordsApoptosis, Coxsackievirus Infections, Enterovirus B, Human, Host-Pathogen Interactions, Humans, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase 7, Necrosis, p38 Mitogen-Activated Protein Kinases, Signal Transduction
Abstract

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.

DOI10.1016/j.chom.2012.11.009
Alternate JournalCell Host Microbe
PubMed ID23332156
PubMed Central IDPMC3553504
Grant List1-DP2-OD006464 / OD / NIH HHS / United States
92214-1 / / Canadian Institutes of Health Research / Canada
97749-1 / / Canadian Institutes of Health Research / Canada
DP2 OD006464 / OD / NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada