Stearoly-CoA desaturase 1 differentiates early and advanced dengue virus infections and determines virus particle infectivity

PLoS Pathog. 2018 Aug 17;14(8):e1007261. doi: 10.1371/journal.ppat.1007261. eCollection 2018 Aug.

Abstract

Positive strand RNA viruses, such as dengue virus type 2 (DENV2) expand and structurally alter ER membranes to optimize cellular communication pathways that promote viral replicative needs. These complex rearrangements require significant protein scaffolding as well as changes to the ER chemical composition to support these structures. We have previously shown that the lipid abundance and repertoire of host cells are significantly altered during infection with these viruses. Specifically, enzymes in the lipid biosynthesis pathway such as fatty acid synthase (FAS) are recruited to viral replication sites by interaction with viral proteins and displayed enhanced activities during infection. We have now identified that events downstream of FAS (fatty acid desaturation) are critical for virus replication. In this study we screened enzymes in the unsaturated fatty acid (UFA) biosynthetic pathway and found that the rate-limiting enzyme in monounsaturated fatty acid biosynthesis, stearoyl-CoA desaturase 1 (SCD1), is indispensable for DENV2 replication. The enzymatic activity of SCD1, was required for viral genome replication and particle release, and it was regulated in a time-dependent manner with a stringent requirement early during viral infection. As infection progressed, SCD1 protein expression levels were inversely correlated with the concentration of viral dsRNA in the cell. This modulation of SCD1, coinciding with the stage of viral replication, highlighted its function as a trigger of early infection and an enzyme that controlled alternate lipid requirements during early versus advanced infections. Loss of function of this enzyme disrupted structural alterations of assembled viral particles rendering them non-infectious and immature and defective in viral entry. This study identifies the complex involvement of SCD1 in DENV2 infection and demonstrates that these viruses alter ER lipid composition to increase infectivity of the virus particles.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Biomarkers
  • Cells, Cultured
  • Chlorocebus aethiops
  • Cricetinae
  • Dengue / diagnosis*
  • Dengue / pathology
  • Dengue / virology
  • Dengue Virus / pathogenicity*
  • Diagnosis, Differential
  • Disease Progression
  • Early Diagnosis
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / virology
  • Host-Pathogen Interactions* / genetics
  • Humans
  • Lipogenesis / genetics
  • Male
  • Stearoyl-CoA Desaturase / genetics
  • Stearoyl-CoA Desaturase / physiology*
  • Vero Cells
  • Virion / pathogenicity
  • Virulence
  • Virus Replication / genetics

Substances

  • Biomarkers
  • Stearoyl-CoA Desaturase

Grant support

The study was funded by the office of the Vice President for Research, College of Veterinary Medicine and Biomedical Sciences, Microbiology, Immunology and Pathology start up contributions to RP and Infectious Disease Research Center Fellowship to RCG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.