Abstract
Flaviviruses include the most prevalent and medically challenging viruses. Persistent infection with flaviviruses of epithelial cells and hepatocytes that do not undergo cell death is common. Here, we report that, in epithelial cells, up-regulation of autophagy following flavivirus infection markedly enhances virus replication and that one flavivirus gene, NS4A, uniquely determines the up-regulation of autophagy. Dengue-2 and Modoc (a murine flavivirus) kill primary murine macrophages but protect epithelial cells and fibroblasts against death provoked by several insults. The flavivirus-induced protection derives from the up-regulation of autophagy, as up-regulation of autophagy by starvation or inactivation of mammalian target of rapamycin also protects the cells against insult, whereas inhibition of autophagy via inactivation of PI3K nullifies the protection conferred by flavivirus. Inhibition of autophagy also limits replication of both Dengue-2 and Modoc virus in epithelial cells. Expression of flavivirus NS4A is sufficient to induce PI3K-dependent autophagy and to protect cells against death; expression of other viral genes, including NS2A and NS4B, fails to protect cells against several stressors. Flavivirus NS4A protein induces autophagy in epithelial cells and thus protects them from death during infection. As autophagy is vital to flavivirus replication in these cells, NS4A is therefore also identified as a critical determinant of flavivirus replication.
Highlights
JUNE 24, 2011 VOLUME 286 NUMBER 25 other cell types and subsequently protects them
NS2A is required for the assembly of new flavivirus virions; NS4A associates with the virus replication complex and induces ER membrane rearrangements, and NS4B is an antagonist of interferon
Modoc Virus Does Not Kill Infected Epithelial Cells or Fibroblasts—The impact of flavivirus on cell fate is specific to cell type; macrophages and neurons die following infection but hepatocytes and fibroblasts survive
Summary
JUNE 24, 2011 VOLUME 286 NUMBER 25 other cell types and subsequently protects them. Only 17% of mock Ϫ infected cells display punctate LC3-GFP (indicating normal housekeeping activity), nearly 70% of both Modoc and Dengue-2 virus-infected cells display LC3-GFP punctation (Fig. 4J), demonstrating that both viruses induce autophagy. Limited amount of LC3-GFP punctation is seen in mock control cells, whereas infection by either Dengue-2 or Modoc virus increases punctation dramatically (to ϳ70%), indicating flavivirus-induced up-regulation of autophagy.
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