Dynamic regulation of autophagy during Semliki Forest virus infection of neuroblastoma cells

Abstract

Autophagy can defend against infection by delivering viruses to lysosomes for degradation. Semliki Forest virus (SFV) is a positive-sense, single-stranded RNA virus of the alphavirus genus which has been used extensively as a model for arbovirus infection and neuronal encephalitis. Here, we show that autophagy is suppressed during the early hours of SFV infection of neurons. We also show that a switch between autophagy suppression and upregulation between the early and later stages was mediated through modulation of the mammalian target of rapamycin (mTOR) activity during infection. At later stages of infection, autophagosomes colocalize with SFV nonstructural proteins suggesting the formation of a platform for virus replication. Inhibition of mTOR by torin reduced infectious virus production and intracellular virus gene expression while improving cell survival during infection. The results suggest that autophagy is suppressed early during infection of neurons to increase cell survival and then upregulated at later times to facilitate replication. This biphasic regulation of autophagy seen for SFV may be important for other arboviruses, and knowledge about the regulation of autophagy by alphaviruses may be useful for the development of antiviral therapies.