Miltefosine inhibits Chikungunya virus replication in human primary dermal fibroblasts.

Anuj Sharma,Tze-Jou Yeh,Manish Bhomia,Jay Singh,Radha K Maheshwari

doi:10.12688/f1000research.13242.1

Anuj Sharma, Tze-Jou Yeh + Show 3 more

Open Access

https://doi.org/10.12688/f1000research.13242.1

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Abstract

Background: Chikungunya virus (CHIKV) is a re-emerging pathogen that has caused widespread outbreaks affecting millions of people around the globe. Currently, there is no specific therapeutic drug against CHIKV, with symptomatic treatment only to manage the disease. Pi3-akt signaling has been implicated in infection of several viruses including that of CHIKV. Effect of Pi3-akt signaling inhibitors on CHIKV replication was evaluated in this study. Methods: Human primary dermal fibroblast cells were treated with inhibitors of the Pi3-akt signaling pathway. Suppression of CHIKV replication was evaluated as reduction in virus titer in cell supernatants. Effect of miltefosine (MF) on CHIKV replication was evaluated in pre and post treatment regimen. Inhibition of virus replication was determined by cell growth, virus titer and western blot. Results: Inhibition of Akt-phosphorylation significantly inhibited CHIKV replication. No effect on CHIKV replication was observed after treatment with Pi3-kinase and mTOR activation inhibitors. Further, MF, an FDA-approved Akt-inhibitor, inhibited CHIKV replication in pre- and post-infection treatment regimens. Conclusion: Data suggests that Akt-phosphorylation can be an amenable target of therapy against CHIKV infection. This is the first study to show inhibition of CHIKV replication by MF, and presents a case for further development of MF as an anti-CHIKV drug.

Highlights

Chikungunya virus (CHIKV) is an Old World alphavirus which has caused widespread outbreaks in tropical countries around the globe[1,2,3,4]
HPDF cells support CHIKV replication: Dermal fibroblast are the target of CHIKV infection[16], replication kinetics of CHIKV181/25 was determined in human primary dermal fibroblast (hPDF)
Treatment with 20 μM and above doses of MF resulted in significant reduction in CHIKV titer in cell supernatants, at multiplicity of infection (MOI)=1, virus titers were significantly higher than the samples infected with MOI=0.1 (Figure 3B)

Summary

Introduction

Chikungunya virus (CHIKV) is an Old World alphavirus which has caused widespread outbreaks in tropical countries around the globe[1,2,3,4]. In this study, the effect of inhibition of Pi3-Akt signaling on CHIKV replication was evaluated in human primary dermal fibroblast (hPDF) cells. HPDF cells were used in this study as dermal fibroblast are one of the primary targets of CHIKV infection[16]. A significant inhibition of CHIKV replication was observed in the hPDF cells treated with MF before and after the infection. Effect of Pi3-akt signaling inhibitors on CHIKV replication was evaluated in this study. MF, an FDA-approved Akt-inhibitor, inhibited CHIKV replication in pre- and post-infection treatment regimens. Conclusion: Data suggests that Akt-phosphorylation can be an amenable target of therapy against CHIKV infection This is the first study to show inhibition of CHIKV replication by MF, and presents a case for further development of MF as an anti-CHIKV drug

Methods

Results

Conclusion