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Research Paper

Direct and indirect pro-inflammatory cytokine response resulting from TC-83 infection of glial cells

ORCID Icon, ORCID Icon, ORCID Icon, , &
Pages 1403-1421 | Received 29 Apr 2018, Accepted 31 Jul 2018, Published online: 03 Sep 2018
 

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.