Activation of PI 3-kinase/Akt/NF-κB and Stat3 signaling by avian reovirus S1133 in the early stages of infection results in an inflammatory response and delayed apoptosis

Abstract

Avian reovirus (ARV) strain S1133 causes apoptosis in host cells in the middle to late stages of infection. This study investigated the early-stage biological response and intracellular signaling in ARV S1133-infected Vero and chicken cells. Treatment with conditioned medium from ARV S1133-infected cells increased the chemotactic activity of U937 cells. Neutralizing antibodies against IL-1beta and IL-6 showed that both cytokines contribute to viral-induced inflammation but neither affect cell survival. Inhibition of Akt, NF-kappaB, and Stat3 released the chemotactic activity and anti-apoptotic effect elicited by ARV S1133. ARV S1133 activated PI 3-kinase-dependent Akt/NF-kappaB and p70 S6 kinase, as well as Stat3; however, p70 S6 kinase was not involved in ARV S1133-mediated effects. DF1 cells over-expressing constitutively active PI 3-kinase and Stat3 showed association with enhancement of anti-apoptotic activity. In conclusion, in the early stages of ARV S1133 infection, activation of cell survival signals contributes to virus-induced inflammation and anti-apoptotic response.

The p17 Nonstructural Protein of Avian Reovirus Triggers Autophagy Enhancing Virus Replication via Activation of Phosphatase and Tensin Deleted on Chromosome 10 (PTEN) and AMP-activated Protein Kinase (AMPK), as well as dsRNA-dependent Protein Kinase (PKR)/eIF2α Signaling Pathways

“…Induction of autophagy has often connected to inhibition of apoptosis. Here, we found that ARV-induced autophagosome at 3 hpi correlates with our previous findings that ARV triggers Akt at 30 min to 2 hpi, resulting in delayed apoptosis in Vero cells (40). It was proved that ARV induces cell death in the middle to late stages of infection (2,40).…”

“…Here, we found that ARV-induced autophagosome at 3 hpi correlates with our previous findings that ARV triggers Akt at 30 min to 2 hpi, resulting in delayed apoptosis in Vero cells (40). It was proved that ARV induces cell death in the middle to late stages of infection (2,40). ARV seems to trigger survival signaling in the early stage of infection that protects the host cells from caspase-dependent apoptotic cell death.…”

“…Our previous study and this work indicated that at the middle to late stages of ARV infection, activation of Akt and mTOR was inhibited in ARV-infected cells. Previously, we have found that Akt is activated by ARV during the early stages of infection (from 30 min to 2 h), and then declined at 3 hpi, resulting in delayed apoptosis in Vero cells (40). The kinetics of Akt and mTOR inhibition correlated with conversion of LC3-I to LC3-II, suggesting a role for Akt and mTOR as negative mediators of ARV-induced autophagy.…”

Critical role of eukaryotic elongation factor 1 alpha 1 (EEF1A1) in avian reovirus sigma-C-induced apoptosis and inhibition of viral growth

“…This observation is consistent with a previous report showing that ARV rC induced apoptosis in cultured cells [10]. Although ARV-induced apoptosis has been reported to be associated with NF-jB [15,16] and p53 [17][18][19], it is still not clear how the viral proteins trigger the apoptotic process. In the present study, we used yeast-two hybrid screening, immunoprecipitation and confocal microscopy assays (Figs.…”

“…The ability of avian reoviruses to induce apoptosis is not restricted to a particular virus strain or to a specific cell type, since different avian reovirus isolates were able to induce apoptosis in several avian and mammalian cell lines [2]. Although it was found that reovirus-induced apoptosis was associated with activation of NF-kappa B [15,16] and p53 [17][18][19] and that r-C of ARV S1133 and p10.8 protein of Muscovy duck reovirus (MDRV) were found to induce apoptosis in cultured cells [10,20], the underlying molecular mechanism of apoptosis is still not fully understood.…”