Tilorone-Dihydrochloride Protects against Rift Valley Fever Virus Infection and Disease in the Mouse Model

Kendra N Johnson,Tetsuro Ikegami,Alexander N Freiberg,Jennifer K Smith,Terry Juelich,Birte Kalveram,Colm Atkins,Lihong Zhang

doi:10.3390/microorganisms10010092

Kendra N Johnson, Tetsuro Ikegami + Show 6 more

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https://doi.org/10.3390/microorganisms10010092

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Abstract

Rift Valley fever (RVF) is a mosquito-borne zoonotic disease endemic to Africa and the Middle East that can affect humans and ruminant livestock. Currently, there are no approved vaccines or therapeutics for the treatment of severe RVF disease in humans. Tilorone-dihydrochloride (Tilorone) is a broad-spectrum antiviral candidate that has previously shown efficacy against a wide range of DNA and RNA viruses, and which is clinically utilized for the treatment of respiratory infections in Russia and other Eastern European countries. Here, we evaluated the antiviral activity of Tilorone against Rift Valley fever virus (RVFV). In vitro, Tilorone inhibited both vaccine (MP-12) and virulent (ZH501) strains of RVFV at low micromolar concentrations. In the mouse model, treatment with Tilorone significantly improved survival outcomes in BALB/c mice challenged with a lethal dose of RVFV ZH501. Treatment with 30 mg/kg/day resulted in 80% survival when administered immediately after infection. In post-exposure prophylaxis, Tilorone resulted in 30% survival at one day after infection when administered at 45 mg/kg/day. These findings demonstrate that Tilorone has potent antiviral efficacy against RVFV infection in vitro and in vivo and supports further development of Tilorone as a potential antiviral therapeutic for treatment of RVFV infection.

Highlights

Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus of the Phenuiviridae family endemic to Sub-Saharan Africa and is the causative agent of Rift Valley fever (RVF) [1,2]
Vero CCL81 cells were grown and maintained in minimal essential media (MEM) and A549 cells were maintained in Dulbecco’s minimal essential media (DMEM), both supplemented with 10% Fetal Bovine Serum (FBS) at 37 ◦ C
Due to the previous reports that Tilorone might act through activation of IFN-related innate immunity signaling pathways [19,28], we chose to evaluate its antiviral activity in both, type-I IFN-deficient Vero CCL81 and type-I IFN-competent A549 cells

Summary

Introduction

Rift Valley fever virus (RVFV) is a mosquito-borne RNA virus of the Phenuiviridae family (order Bunyavirales) endemic to Sub-Saharan Africa and is the causative agent of Rift Valley fever (RVF) [1,2]. RVF is most commonly a disease of domestic ruminants such as cattle, goats, and sheep, primarily presenting as an acute fever [3]. In susceptible species, such as sheep, it causes fetal malformation and abortion storm in pregnant animals and has high newborn mortality rates up to 100% [3]. Along with regular outbreaks in livestock, RVF causes spillover events into human populations [4,5,6,7,8]. Most human cases of RVF present as a self-limiting febrile illness.

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