https://orcid.org/0000-0001-6052-4867
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ABSTRACT
Venezuelan equine encephalitis virus (VEEV) is a neurotropic arbovirus that is highly infectious as an aerosol and can result in an encephalitic phenotype in infected individuals. VEEV infections are known to be associated with robust inflammation that eventually contributes to neurodegenerative phenotypes. In this study, we utilize the TC-83 strain of VEEV, which is known to induce the expression of IL-6, IL-8, and other pro-inflammatory cytokines. We had previously demonstrated that TC-83 infection resulted in changes in mitochondrial function, eventually resulting in mitophagy. In this manuscript, we provide data that links upstream mitochondrial dysfunction with downstream pro-inflammatory cytokine production in the context of microglia and astrocytoma cells. We also provide data on the role of bystander cells, which significantly contribute to the overall inflammatory load. Use of a mitochondrial-targeted antioxidant, mitoquinone mesylate, greatly reduced the inflammatory cytokine load and ameliorated bystander cell inflammatory responses more significantly than a broad-spectrum anti-inflammatory compound (BAY 11–7082). Our data suggest that the inflammatory mediators, especially IL-1β, may prime naïve cells to infection and lead to increased infection rates in microglial and astrocytoma cells. Cumulatively, our data suggest that the interplay between mitochondrial dysfunction and inflammatory events elicited in a neuronal microenvironment during a TC-83 infection may contribute to the spread of infection.
Abbreviations
| BAY-82 | = | anti-inflammatory molecule BAY-11–7082 |
| BBB | = | blood brain barrier |
| DCFDA | = | 2ʹ,7ʹ-dichlorofluorescin diacetate |
| FCCP | = | carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone |
| GSK-3β | = | glycogen synthase kinase-3β |
| IFN | = | interferon |
| IL | = | interleukin |
| JEV | = | Japanese encephalitis virus |
| MitoQ | = | mitoquinone mesylate |
| MMP | = | mitochondrial membrane potential |
| RNA | = | ribonucleic acid |
| ROS | = | reactive oxygen species |
| RT-PCR | = | real time polymerase chain reaction |
| TBHP | = | tert-butyl hydrogen peroxide |
| TC-83 | = | attenuated strain of Venezuelan equine encephalitis virus |
| TMRE | = | tetramethylrhodamine, ethyl ester |
| TNFα | = | tumor necrosis factor α |
| VEEV | = | Venezuelan equine encephalitis virus |
Acknowledgments
The authors would like to acknowledge Dr. Shin Chao Lin, Daud Khan and Stephen Roberts for their assistance and Leidos for their support of the inflammatory cytokine arrays. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Disclosure statement
No potential conflict of interest was reported by the authors.
Supplementary material
Supplemental data for this article can be accessed here.