Down regulation ofHmgcrin response to Influenza A infection is independent of the IFN response in human cells

Abstract

Previous studies have demonstrated that the product of the Interferon stimulated gene Ch25h, 25-Hydroxycholestrol, provides an immediate and rapid mechanism for down-regulating sterol biosynthesis, through the inhibition of Hmgcr gene expression and proteolytic degradation of HMGCR protein. Further studies provide evidence that inhibition of the sterol biosynthesis pathway by 25-HC has broad antiviral effects. In this study, Influenza A virus (IAV) replication was inhibited in cells treated with Fluvastatin or where Hmgcr expression was inhibited with an siRNA. Treatment of A549 cells with 25-HC however, resulted in a 2-fold enhancement of IAV replication despite the fact that 25-HC promotes the proteolytic degradation of HMGCR. A549 cells infected with IAV revealed a rapid loss of HMGCR protein, a reduction in Hmgcr gene expression as well as an increase in the expression of Ch25h, that were all independent of the IFN pathway.Infection of both wild-type and Ch25h -/murine BMDMs with IAV also revealed a rapid loss of HMGCR abundance indicating that 25-HC independent mechanisms exist for promoting proteolytic degradation of HMGCR. These data for the human A549 cell line contrast with the induction of Ch25h and subsequent loss of HMGCR in murine cells that has been shown to be dependent on IFN signalling.

Modulating cholesterol-rich lipid rafts to disrupt influenza A virus infection

“…In addition, cholesterol is known to modulate IAV trafficking, and depletion of cholesterol disrupts IAV transport after cellular entry ( 60 , 62 , 64 , 76 ). Mehrbod et al ( 62 ) showed that simvastatin prevents RhoA prenylation, which is key to arrangement of the actin cytoskeleton for endosome trafficking, and results in inefficient transport of viral genomes into the nucleus for replication ( Figure 1 ).…”

“…In addition, cholesterol is known to modulate IAV trafficking, and depletion of cholesterol disrupts IAV transport after cellular entry (60, 62,64,76). Mehrbod et al (62) showed that simvastatin prevents RhoA prenylation, which is key to Effect of statins on the IAV life cycle and the host immune response.…”