Abstract
Despite the importance of Dengue virus (DENV) infection in human health, there is not a fully effective vaccine or antiviral treatment against the infection. Since lipids such as cholesterol are required during DENV infection, its uptake and synthesis are increased in infected cells. Ezetimibe is an FDA-approved drug that reduces cholesterol uptake by inhibiting the endocytosis through Niemman-Pick C1-Like 1 (NPC1L1) receptor, expressed on the membrane of enterocytes and hepatocytes. Our results indicate that an increase in the amount of NPC1L1 occurs on the surface of Huh-7 cells during DENV infection, which correlates with an increase in cholesterol levels. Blockage of NPC1L1 with ezetimibe in concentrations up to 50 μM does not reduce cell viability but diminished total cellular cholesterol, the percentage of infected cells, viral yield, viral RNA and protein synthesis without affecting DENV binding and/or entry to Huh-7 cells. Moreover, ezetimibe inhibited DENV replicative complex formation and lipid droplets accumulation. All these results indicate that ezetimibe is an excellent drug to inhibit DENV infection and confirm that cholesterol is a key target to inhibit viral infection.
Highlights
Dengue is a systemic infection caused by dengue virus (DENV), a member of the Flaviviridae family and Flavivirus genus, that includes four serotypes (DENV 1 to DENV 4) (Guzman and Harris, 2015)
Since the main role of the Niemann-Pick C1-Like 1 (NPC1L1) receptor is the cholesterol uptake, and cholesterol is essential for DENV infection, the first step was to determine if this receptor was present on the cell surface during DENV infection
Treatment with statins, which inhibit the activity of HMG-CoA reductase, or metformin which activates APMK in cellular and/or animal models appears promising against DENV infection aCC-BY 4.0 International license. (Martinez-Gutierrez et al, 2014; Rothwell et al, 2009b; Soto-Acosta et al, 2017, 2013)
Summary
Dengue is a systemic infection caused by dengue virus (DENV), a member of the Flaviviridae family and Flavivirus genus, that includes four serotypes (DENV 1 to DENV 4) (Guzman and Harris, 2015). There are no specific drugs to treat the infection with DENV or a fully effective vaccine Viral factors such as the high genetic variability among the four serotypes of DENV (Lim et al, 2013), antibody-dependent enhancement (ADE), and cross-reactivity with other Flavivirus such as Zika virus, make difficult to obtain a fully effective vaccine (Halstead and Russell, 2016; Villar et al, 2015). For this reason, development of therapeutic strategies with a pan-serotype effect is a priority. Our results indicate that NPC1L1 receptor participates actively in the cholesterol uptake during DENV infection and that the drug ezetimibe inhibits DENV infection in the human hepatoma cell line (Huh-7) by blocking the NPC1L1 receptor
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