Statin-mediated disruption of Rho GTPase prenylation and activity inhibits respiratory syncytial virus infection

  • Commun Biol. 2021 Oct 29;4(1):1239. doi: 10.1038/s42003-021-02754-2.
Manpreet Malhi  1  2 ,  Michael J Norris  3  4 ,  Wenming Duan  4 ,  Theo J Moraes  3  4  5 ,  Jason T Maynes  6  7  8
Affiliations
  • 1. Department of Biochemistry, University of Toronto, Toronto, ON, Canada.
  • 2. Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
  • 3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • 4. Program in Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
  • 5. Department of Paediatrics, Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
  • 6. Department of Biochemistry, University of Toronto, Toronto, ON, Canada. [email protected].
  • 7. Program in Molecular Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 8. Department of Anesthesia and Pain Medicine, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
PMID: 34716403 DOI: 10.1038/s42003-021-02754-2
Abstract

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new Antiviral therapies, we developed a live cell-based high content screening approach for rapid identification of RSV inhibitors and characterized five drug classes which inhibit the virus. Among the molecular targets for each hit, there was a strong functional enrichment in lipid metabolic pathways. Modulation of lipid metabolites by statins, a key hit from our screen, decreases the production of infectious virus through a combination of Cholesterol and isoprenoid-mediated effects. Notably, RSV Infection globally upregulates host protein prenylation, including the prenylation of Rho GTPases. Treatment by statins or perillyl alcohol, a geranylgeranyltransferase inhibitor, reduces Infection in vitro. Of the Rho GTPases assayed in our study, a loss in Rac1 activity strongly inhibits the virus through a decrease in F protein surface expression. Our findings provide new insight into the importance of host lipid metabolism to RSV Infection and highlight geranylgeranyltransferases as an Antiviral target for therapeutic development.

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