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

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.

A scoping review of Chikungunya virus infection: epidemiology, clinical characteristics, viral co-circulation complications, and control

“…Silymarin interferes with post-entry stages of CHIKV infection, reducing, in a dose dependent manner, the nsP1, nsP3 and E2 proteins production. (Lani et al, 2015) Ribavirin Wichit et al, 2017). Examples of drugs and compounds under evaluation are available on Table 3.…”

Baculovirus utilizes cholesterol transporter Niemann–Pick C1 for host cell entry

“…To investigate whether BmNPC1 is involved in BmNPV infection in insect cells, we first examined the effect of two small molecule NPC1 antagonists on BmNPV-GFP infection in BmE cells. Both small molecules (imipramine and U18666A) have previously been shown to mimic the molecular phenotype of NPC disease and block the exit of cholesterol from late endosomal compartments (17, 27). BmE cells were pretreated with imipramine (25-100 μM for 2 h) or U18666A (0.5 to 10 μM for 24 h) before the addition of BmNPV viral inoculum.…”

“…Interestingly, in addition to Ebola virus (family: Filoviridae ), hepatitis C virus (family: Flaviviridae ) entry also requires the cholesterol trafficking receptor Niemann-Pick C1-Like 1 (NPC1L1) (31), a NPC1 paralog which serves in cellular cholesterol absorption and homeostasis on the apical surface of intestinal enterocytes and human hepatocytes (20, 32). Moreover, the release of HIV-1 (family: Retroviridae ) (33) and Chikungunya virus (family: Togaviridae ) (27) is impaired in cells from patients with NPC disease. U18666A or imipramine, which mimics a NPC-deficient phenotype, also strongly inhibits the replication of several flaviviridae family members, including Zika, West Nile, and Dengue viruses (27).…”

“…Moreover, the release of HIV-1 (family: Retroviridae ) (33) and Chikungunya virus (family: Togaviridae ) (27) is impaired in cells from patients with NPC disease. U18666A or imipramine, which mimics a NPC-deficient phenotype, also strongly inhibits the replication of several flaviviridae family members, including Zika, West Nile, and Dengue viruses (27). In our study, we present evidence that baculovirus utilizes the NPC1 homolog to enter into insect cells.…”

“…Here, we demonstrate that BV of BmNPV infection requires the expression of BmNPC1. BmE cells pre-treated with the NPC1 inhibitors imipramine or U18666A, which can mimic the molecular phenotype of NPC disease (26, 27), results in marked inhibition of viral replication and production. Silencing, knocking out of BmNPC1 expression or blocking BmNPC1 function with domain-specific antibodies also substantially impairs BmNPV proliferation in vitro .…”