Efficacy of FDA-Approved Anti-Inflammatory Drugs Against Venezuelan Equine Encephalitis Virus Infection.

Kenneth Risner,Aslaa Ahmed,Stephanie Kortchak,Nishank Bhalla,Allison Bakovic,Aarthi Narayanan

doi:10.3390/v11121151

Kenneth Risner, Aslaa Ahmed + Show 4 more

Open Access

https://doi.org/10.3390/v11121151

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Journal: Viruses	Publication Date: Dec 12, 2019
Citations: 17	License type: CC BY 4.0

Affiliation: George Mason University

Abstract

Venezuelan equine encephalitis virus (VEEV) is a category B select agent pathogen that can be aerosolized. Infections in murine models and humans can advance to an encephalitic phenotype which may result in long-term neurological complications or death. No specific FDA-approved treatments or vaccines are available for the treatment or prevention of VEEV infection. Neurotropic viral infections have two damaging components: neuronal death caused by viral replication, and damage from the subsequent inflammatory response. Reducing the level of inflammation may lessen neurological tissue damage that often arises following VEEV infection. In this study, three commercially available anti-inflammatory drugs, Celecoxib, Rolipram, and Tofacitinib, were evaluated for antiviral activity in an astrocyte and a microglial model of VEEV infection. The inhibitors were tested against the vaccine strain VEEV TC-83, as well as the wild-type VEEV Trinidad donkey strain. Celecoxib, Tofacitinib, and Rolipram significantly decreased viral titers both after pre-treatment and post-treatment of infected cells. VEEV Trinidad Donkey (TrD) titers were reduced 6.45-fold in cells treated with 50 µM of Celecoxib, 2.45-fold when treated with 50 µM of Tofacitinib, and 1.81-fold when treated with 50 µM of Rolipram. Celecoxib was also shown to decrease inflammatory gene expression in the context of TC-83 infection. Overall, Celecoxib demonstrated potency as a countermeasure strategy that slowed VEEV infection and infection-induced inflammation in an in vitro model.

Highlights

Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus endemic to the Americas [1].VEEV is a New World (NW) alphavirus of the family Togaviridae and is classified as a Group IV (+)ssRNA virus
We used HMC3 human-derived microglia to evaluate the effects of various drugs on VEEV infection using a previously established model [23]
At a concentration of 50 μM, Celecoxib, Rolipram, and Tofacitinib demonstrated low toxicity with cell survival at >90% (Figure 1A–C), whereas increasing toxicity was observed at a higher concentration

Summary

Introduction

Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus endemic to the Americas [1].VEEV is a New World (NW) alphavirus of the family Togaviridae and is classified as a Group IV (+)ssRNA virus. VEEV is categorized as a select agent pathogen by the Centers for Disease Control and the United States Department of Agriculture due to its potential for being weaponized as a consequence of a very low infective dose and an ability to be aerosolized [2]. Mosquito-transmitted infections can occur at doses as low as 10 to 1000 PFU [4]. As an RNA virus, VEEV has the potential to quickly generate novel mutations that may allow for epidemic spread by its mosquito vectors. Mutations in the E1 glycoprotein of Chikungunya virus (CHIKV), a related alphavirus, led to increased fitness in mosquitoes which caused a worldwide pandemic that still persists today [6].

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