Imipramine Inhibits Chikungunya Virus Replication in Human Skin Fibroblasts through Interference with Intracellular Cholesterol Trafficking

• Published in: Scientific reports Vol. 7; no. 1; pp. 3145 - 12
• Main Authors: Wichit, Sineewanlaya, Hamel, Rodolphe, Bernard, Eric, Talignani, Loïc, Diop, Fodé, Ferraris, Pauline, Liegeois, Florian, Ekchariyawat, Peeraya, Luplertlop, Natthanej, Surasombatpattana, Pornapat, Thomas, Frédéric, Merits, Andres, Choumet, Valérie, Roques, Pierre, Yssel, Hans, Briant, Laurence, Missé, Dorothée
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.06.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/44; 13/51; 14; 42; 45; 631/154/555; 692/699/255/2514; 82; 82/1; 82/29; Androstenes; Androstenes - pharmacology; Biochemistry, Molecular Biology; Biological Transport; Biological Transport - drug effects; Cells, Cultured; Cellular Biology; Chikungunya virus; Chikungunya virus - drug effects; Cholesterol; Cholesterol - metabolism; Chukungunya Virus; Cytotoxicity; Dengue fever; Fibroblasts; Fibroblasts - cytology; Fibroblasts - virology; Humanities and Social Sciences; Humans; Imipramine; Imipramine - pharmacology; Intracellular; Life cycles; Life Sciences; Molecular biology; multidisciplinary; Niemann-Pick disease; Niemann-Pick Disease, Type C; Niemann-Pick Disease, Type C - pathology; Replication; Science; Science (multidisciplinary); Skin; Skin - cytology; Skin - drug effects; Skin - virology; Subcellular Processes; Vector-borne diseases; Viral infections; Virus Internalization; Virus Internalization - drug effects; Virus Replication; Virus Replication - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-03316-5

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.