Combination Kinase Inhibitor Treatment Suppresses Rift Valley Fever Virus Replication.

Todd Bell,Chelsea Pinkham,Kylene Kehn-Hall,Brian Carey,Lance Liotta,Cynthia De La Fuente,Shih-Chao Lin,Ashwini Brahms,Caitlin Woodson,Virginia Espina,Charles Bailey,Lindsay Lundberg,Bibha Dahal

doi:10.3390/v10040191

Abstract

Viruses must parasitize host cell translational machinery in order to make proteins for viral progeny. In this study, we sought to use this signal transduction conduit against them by inhibiting multiple kinases that influence translation. Previous work indicated that several kinases involved in translation, including p70 S6K, p90RSK, ERK, and p38 MAPK, are phosphorylated following Rift Valley fever virus (RVFV) infection. Furthermore, inhibiting p70 S6K through treatment with the FDA approved drug rapamycin prevents RVFV pathogenesis in a mouse model of infection. We hypothesized that inhibiting either p70 S6K, p90RSK, or p90RSK’s upstream kinases, ERK and p38 MAPK, would decrease translation and subsequent viral replication. Treatment with the p70 S6K inhibitor PF-4708671 resulted in decreased phosphorylation of translational proteins and reduced RVFV titers. In contrast, treatment with the p90RSK inhibitor BI-D1870, p38MAPK inhibitor SB203580, or the ERK inhibitor PD0325901 alone had minimal influence on RVFV titers. The combination of PF-4708671 and BI-D1870 treatment resulted in robust inhibition of RVFV replication. Likewise, a synergistic inhibition of RVFV replication was observed with p38MAPK inhibitor SB203580 or the ERK inhibitor PD0325901 combined with rapamycin treatment. These findings serve as a proof of concept regarding combination kinase inhibitor treatment for RVFV infection.

Highlights

Rift Valley fever virus (RVFV), an emerging pathogen and public health threat, was identified as the causative agent of an outbreak of viral hemorrhagic fever in Kenya in 1930 [1,2]
Inhibitors targeting phosphorylation of 70-kDa S6 kinase (p70 S6K) and p90RSK either alone or in combination were evaluated to determine if they influenced RVFV replication in mouse hepatocytes
H2.35 BALB/c hepatocytes were somewhat tolerant of the p70 S6K inhibitor PF-4708671, with a Concentration 50 (CC50) of over 50 μM

Summary

Introduction

Rift Valley fever virus (RVFV), an emerging pathogen and public health threat, was identified as the causative agent of an outbreak of viral hemorrhagic fever in Kenya in 1930 [1,2]. The alarming escape of other arthropod-borne viruses (West Nile virus, chikungunya virus, Zika virus) from their ecological niches, into and throughout the Americas [19,20,21,22,23,24] gives us a potential harbinger of future events. Based on these concerning trends, governments and public health authorities across the globe have identified a need for FDA approved vaccines and treatments for RVFV [1,25].

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