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Characterization of Brain Inflammation, Apoptosis, Hypoxia, Blood-Brain Barrier Integrity and Metabolism in Venezuelan Equine Encephalitis Virus (VEEV TC-83) Exposed Mice by In Vivo Positron Emission Tomography Imaging

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Translational Sciences Directorate, Countermeasure Development Division, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Ft. Detrick, MD 21702, USA
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Cherokee Nation Assurance, 777 West Cherokee Street, Catoosa, OK 74015, USA
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Foundational Sciences Directorate, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Ft. Detrick, MD 21702, USA
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General Dynamics Information Technology (GDIT), 3211 Jermantown Road, Fairfax, VA 22030, USA
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Foundational Sciences Directorate, Virology Division, U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter St., Ft. Detrick, MD 21702, USA
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Imaging Probe Development Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Immunodiagnostic Department, Naval Medical Research Center, 8400 Research Plaza, Fort Detrick, MD 21702, USA
*
Author to whom correspondence should be addressed.
Viruses 2019, 11(11), 1052; https://doi.org/10.3390/v11111052
Received: 9 September 2019 / Revised: 23 October 2019 / Accepted: 7 November 2019 / Published: 13 November 2019
(This article belongs to the Section Animal Viruses)
Traditional pathogenesis studies of alphaviruses involves monitoring survival, viremia, and pathogen dissemination via serial necropsies; however, molecular imaging shifts this paradigm and provides a dynamic assessment of pathogen infection. Positron emission tomography (PET) with PET tracers targeted to study neuroinflammation (N,N-diethyl-2-[4-phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide, [18F]DPA-714), apoptosis (caspase-3 substrate, [18F]CP-18), hypoxia (fluormisonidazole, [18F]FMISO), blood–brain barrier (BBB) integrity ([18F]albumin), and metabolism (fluorodeoxyglucose, [18F]FDG) was performed on C3H/HeN mice infected intranasally with 7000 plaque-forming units (PFU) of Venezuelan equine encephalitis virus (VEEV) TC-83. The main findings are as follows: (1) whole-brain [18F]DPA-714 and [18F]CP-18 uptake increased three-fold demonstrating, neuroinflammation and apoptosis, respectively; (2) [18F]albumin uptake increased by 25% across the brain demonstrating an altered BBB; (3) [18F]FMISO uptake increased by 50% across the whole brain indicating hypoxic regions; (4) whole-brain [18F]FDG uptake was unaffected; (5) [18F]DPA-714 uptake in (a) cortex, thalamus, striatum, hypothalamus, and hippocampus increased through day seven and decreased by day 10 post exposure, (b) olfactory bulb increased at day three, peaked day seven, and decreased day 10, and (c) brain stem and cerebellum increased through day 10. In conclusion, intranasal exposure of C3H/HeN mice to VEEV TC-83 results in both time-dependent and regional increases in brain inflammation, apoptosis, and hypoxia, as well as modest decreases in BBB integrity; however, it has no effect on brain glucose metabolism. View Full-Text
Keywords: alphaviruses; Venezuelan equine encephalitis; VEEV TC-83; C3H/HeN mice; PET imaging; neuroinflammation; apoptosis; hypoxia; BBB integrity; glucose metabolism; [18F]DPA-714; [18F]CP-18; [18F]FMISO; [18F]albumin; [18F]FDG alphaviruses; Venezuelan equine encephalitis; VEEV TC-83; C3H/HeN mice; PET imaging; neuroinflammation; apoptosis; hypoxia; BBB integrity; glucose metabolism; [18F]DPA-714; [18F]CP-18; [18F]FMISO; [18F]albumin; [18F]FDG
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Bocan, T.M.; Stafford, R.G.; Brown, J.L.; Akuoku Frimpong, J.; Basuli, F.; Hollidge, B.S.; Zhang, X.; Raju, N.; Swenson, R.E.; Smith, D.R. Characterization of Brain Inflammation, Apoptosis, Hypoxia, Blood-Brain Barrier Integrity and Metabolism in Venezuelan Equine Encephalitis Virus (VEEV TC-83) Exposed Mice by In Vivo Positron Emission Tomography Imaging. Viruses 2019, 11, 1052.

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