Inhibition of Chikungunya Virus Replication in Primary Human Fibroblasts by Liver X Receptor Agonist

The mosquito-borne chikungunya virus (CHIKV) causes acute pain and joint inflammation, and in recent years the virus has caused large epidemics in previously CHIKV-free geographic areas. ABSTRACT The mosquito-borne chikungunya virus (CHIKV) causes acute pain and joint inflammation, and in recent years the virus has caused large epidemics in previously CHIKV-free geographic areas. To advance the understanding of host factors that antagonize CHIKV, we show that synthetic agonist of liver X receptor (LXR-623) inhibits CHIKV replication by upregulating the cholesterol exporter ABCA1 and that endogenous and pharmacological activation of interferon signaling pathway partners with LXR-623 to generate a superior antiviral state.

[1]  K. Moore,et al.  Cholesterol Efflux Pathways Suppress Inflammasome Activation, NETosis, and Atherogenesis , 2018, Circulation.

[2]  E. Amir,et al.  Comprehensive innate immune profiling of chikungunya virus infection in pediatric cases , 2018, Molecular systems biology.

[3]  M. Febbraio,et al.  Defective cholesterol metabolism in haematopoietic stem cells promotes monocyte-driven atherosclerosis in rheumatoid arthritis , 2018, European heart journal.

[4]  M. Puszczewicz,et al.  Chikungunya virus: a rheumatologist's perspective. , 2018, Clinical and experimental rheumatology.

[5]  Lara J. Herrero,et al.  Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation , 2017, Nature Microbiology.

[6]  Penny A. Rudd,et al.  Chikungunya virus: an update on the biology and pathogenesis of this emerging pathogen. , 2017, The Lancet. Infectious diseases.

[7]  G. Hon,et al.  An LXR-Cholesterol Axis Creates a Metabolic Co-Dependency for Brain Cancers. , 2016, Cancer cell.

[8]  Dianfan Li,et al.  Cholesterol homeostasis: How do cells sense sterol excess? , 2016, Chemistry and physics of lipids.

[9]  Peter Tontonoz,et al.  Liver X receptors in lipid metabolism: opportunities for drug discovery , 2014, Nature Reviews Drug Discovery.

[10]  L. Solt,et al.  A liver-selective LXR inverse agonist that suppresses hepatic steatosis. , 2013, ACS chemical biology.

[11]  P. Gasque,et al.  Arthritogenic alphaviruses—an overview , 2012, Nature Reviews Rheumatology.

[12]  P. Roques,et al.  Chikungunya Disease: Infection-Associated Markers from the Acute to the Chronic Phase of Arbovirus-Induced Arthralgia , 2012, PLoS neglected tropical diseases.

[13]  M. Arisawa,et al.  An orally available, small-molecule interferon inhibits viral replication , 2012, Scientific Reports.

[14]  Alain Michault,et al.  Type I IFN controls chikungunya virus via its action on nonhematopoietic cells , 2010, The Journal of experimental medicine.

[15]  M. Prevost,et al.  Characterization of Reemerging Chikungunya Virus , 2007, PLoS pathogens.

[16]  M. Kielian,et al.  Cholesterol is required in the exit pathway of Semliki Forest virus , 1993, The Journal of cell biology.

[17]  M. Kielian,et al.  Cholesterol is required for infection by Semliki Forest virus , 1991, The Journal of cell biology.

[18]  C. Gahmberg,et al.  The lipid class composition of Semliki forest virus and plasma membranes of the host cells. , 1971, Virology.

[19]  R. Ross.  The Newala epidemic: III. The virus: isolation, pathogenic properties and relationship to the epidemic , 1956, Journal of Hygiene.

[20]  M. Fessler.  The challenges and promise of targeting the Liver X Receptors for treatment of inflammatory disease , 2018, Pharmacology & therapeutics.