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Abstract
BackgroundWe 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-α. Since TNF-α is involved in the pathogenesis of hantavirus-caused hemorrhagic fever with renal syndrome (HFRS) we investigated its effects on HFRS-causing hantavirus-infected cells.ResultsWe 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-α. The fold of ERK1/2 inhibition correlated with viral replication efficiencies, which varied drastically between the hantaviruses studied.ConclusionWe demonstrate that in the presence of a cytokine TNF-α, 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.
Highlights
We have previously reported that the apathogenic Tula hantavirus induces apoptosis in Vero E6 epithelial cells
The treatment of Vero E6 cells with a high concentration of Tumor necrosis factor-α (TNF-α) resulted in a similar level of apoptosis and reduction of external signal-regulated kinases 1 and 2 (ERK1/2) activity compared to cells infected with 0.5 multiplicity of infection (MOI) of TULV (Figure 1B)
This in turn suggested that the higher level of ERK1/2 inactivation which was seen in cells infected with MOIs from 1 to 0.2, as compared to lower MOIs used, was due to viral replication and due to induced apoptosis
Summary
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. Hantaviruses (Family Bunyaviridae, Genus Hantavirus) are viruses which chronically infect rodents and insectivores with no apparent disease but in humans they cause two major clinical symptoms: HFRS in Eurasia and hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The strong similarity of these effects to the manifestations in hantavirus diseases [8], together with the evidence of association of TNF-α polymorphism of high-producer haplotype in the severe course of PUUV infection [9], makes TNF-α a factor in hantavirus pathogenesis which deserves further attention. TNF-α-induced programmed cell death occurs via the cleavage of procaspase-8 to its active form, thereby initiating the caspase cascade leading to poly ADP-ribose polymerase (PARP) cleavage among others and eventually apoptosis [10]
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