Hantaviruses and TNF-alpha act synergistically to induce ERK1/2 inactivation in Vero E6 cells.
BACKGROUND
We have previously reported that the apathogenic Tula hantavirus induces apoptosis in Vero E6 epithelial cells. To assess the molecular mechanisms behind the induced apoptosis we studied the effects of hantavirus infection on cellular signaling pathways which promote cell survival. We previously also observed that the Tula virus-induced cell death process is augmented by external TNF-alpha. Since TNF-alpha is involved in the pathogenesis of hantavirus-caused hemorrhagic fever with renal syndrome (HFRS) we investigated its effects on HFRS-causing hantavirus-infected cells.


RESULTS
We studied both apathogenic (Tula and Topografov) and pathogenic (Puumala and Seoul) hantaviruses for their ability to regulate cellular signaling pathways and observed a direct virus-mediated down-regulation of external signal-regulated kinases 1 and 2 (ERK1/2) survival pathway activity, which was dramatically enhanced by TNF-alpha. The fold of ERK1/2 inhibition correlated with viral replication efficiencies, which varied drastically between the hantaviruses studied.


CONCLUSIONS
We demonstrate that in the presence of a cytokine TNF-alpha, which is increased in HFRS patients, hantaviruses are capable of inactivating proteins that promote cell survival (ERK1/2). These results imply that hantavirus-infected epithelial cell barrier functions might be compromised in diseased individuals and could at least partially explain the mechanisms of renal dysfunction and the resulting proteinuria seen in HFRS patients.
Strandin
Tomas
T
Department of Virology, Haartman Institute, P,O, Box 21, FI-00014, University of Helsinki, Finland. tomas.strandin@helsinki.fi
Hepojoki
Jussi
J
Wang
Hao
H
Vaheri
Antti
A
Lankinen
Hilkka
H
D000818:Animals; D017209:Apoptosis; D002522:Chlorocebus aethiops; D006476:Orthohantavirus / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014709:Vero Cells
D014409:Tumor Necrosis Factor-alpha; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3