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

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...

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Published inScientific 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
LanguageEnglish
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
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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.
AbstractList 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.
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.
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.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.
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.
ArticleNumber 3145
Author Diop, Fodé
Luplertlop, Natthanej
Surasombatpattana, Pornapat
Ferraris, Pauline
Choumet, Valérie
Liegeois, Florian
Roques, Pierre
Missé, Dorothée
Talignani, Loïc
Thomas, Frédéric
Bernard, Eric
Ekchariyawat, Peeraya
Merits, Andres
Hamel, Rodolphe
Wichit, Sineewanlaya
Briant, Laurence
Yssel, Hans
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https://pasteur.hal.science/pasteur-01570216$$DView record in HAL
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Snippet 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...
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...
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...
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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
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Title Imipramine Inhibits Chikungunya Virus Replication in Human Skin Fibroblasts through Interference with Intracellular Cholesterol Trafficking
URI https://link.springer.com/article/10.1038/s41598-017-03316-5
https://www.ncbi.nlm.nih.gov/pubmed/28600536
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