Abstract
Chikungunya virus (CHIKV) is an emerging arbovirus of the Togaviridae family that poses a present worldwide threat to human in the absence of any licensed vaccine or antiviral treatment to control viral infection. Here, we show that compounds interfering with intracellular cholesterol transport have the capacity to inhibit CHIKV replication in human skin fibroblasts, a major viral entry site in the human host. Pretreatment of these cells with the class II cationic amphiphilic compound U18666A, or treatment with the FDA-approved antidepressant drug imipramine resulted in a near total inhibition of viral replication and production at the highest concentration used without any cytotoxic effects. Imipramine was found to affect both the fusion and replication steps of the viral life cycle. The key contribution of cholesterol availability to the CHIKV life cycle was validated further by the use of fibroblasts from Niemann-Pick type C (NPC) patients in which the virus was unable to replicate. Interestingly, imipramine also strongly inhibited the replication of several Flaviviridae family members, including Zika, West Nile and Dengue virus. Together, these data show that this compound is a potential drug candidate for anti-arboviral treatment.
Highlights
Chikungunya virus (CHIKV) is an arbovirus transmitted by the genus Aedes spp. that causes chikungunya fever, an infectious disease characterized by myalgia, joint pain, rash, and intense asthenia disease[1, 2]
Depletion of cholesterol in competent cells using methyl β-cyclodextrin was reported to strongly inhibit CHIKV infection[14], which is in line with the generally accepted idea that cholesterol is required for optimal cell membrane fusion, viral replication and budding of prototype alphaviruses, such as Sindbis virus[17] and CHIKV18, as well as other arboviruses, including West Nile virus (WNV), Japanese encephalitis virus and dengue virus (DENV)[19,20,21,22]
In order to examine whether CHIKV replication was dependent on the accumulation of intracellular cholesterol, the human skin fibroblast cell line HFF1 was pre-treated with vehicle or U18666A for 24 h before infection with CHIKV La Réunion strain
Summary
Chikungunya virus (CHIKV) is an arbovirus transmitted by the genus Aedes spp. that causes chikungunya fever, an infectious disease characterized by myalgia, joint pain, rash, and intense asthenia disease[1, 2]. CHIKV is internalized into human target cells as a result of receptor-mediated endocytosis that involves both clathrin-dependent and independent mechanisms[13, 14] and is subsequently delivered to early endosomes from which the virus capsid is released into the cytosol through the formation of fusion pores. The latter process is triggered by the low-pH environment in the endosome that induces an irreversible change in glycoprotein conformation and a dissociation of the E2/E1 heterodimers, followed by E1 trimerizations[11]. Their importance is underscored by the observation that mutations in either one of the NPC1 or NPC2 genes may lead to loss of function of these two endosomal membrane proteins, resulting in the development of NPC disease, a rare, but fatal, autosomal recessive, lysosomal storage disorder, characterized by an accumulation of cholesterol, sphingomyelin, sphingosine, as well as the GM1 and GM3 gangliosides within the LE/Ls25
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