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

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 targe...

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Bibliographic Details
Published in:Viruses 2019-11, Vol.11 (11), p.1052
Main Authors: Bocan, Thomas M, Stafford, Robert G, Brown, Jennifer L, Akuoku Frimpong, Justice, Basuli, Falguni, Hollidge, Bradley S, Zhang, Xiang, Raju, Natarajan, Swenson, Rolf E, Smith, Darci R
Format: Article
Language:English
Subjects:
Aerosols
Albumin
Alzheimer's disease
Animals
Apoptosis
Blood-brain barrier
Brain
Brain stem
Caspase-3
Cerebellum
Encephalitis
Glucose
Glucose metabolism
Hypothalamus
Hypoxia
Infections
Infectious diseases
Inflammation
Laboratories
Metabolism
Mortality
Neostriatum
Neuroimaging
Olfactory bulb
Pathogens
Polyethylene glycol
Positron emission tomography
Thalamus
Tomography
Vaccines
Venezuelan equine encephalitis
Viral infections
Viremia
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Summary: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 ( , -diethyl-2-[4-phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide, [ F]DPA-714), apoptosis (caspase-3 substrate, [ F]CP-18), hypoxia (fluormisonidazole, [ F]FMISO), blood-brain barrier (BBB) integrity ([ F]albumin), and metabolism (fluorodeoxyglucose, [ F]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 [ F]DPA-714 and [ F]CP-18 uptake increased three-fold demonstrating, neuroinflammation and apoptosis, respectively; (2) [ F]albumin uptake increased by 25% across the brain demonstrating an altered BBB; (3) [ F]FMISO uptake increased by 50% across the whole brain indicating hypoxic regions; (4) whole-brain [ F]FDG uptake was unaffected; (5) [ F]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.
ISSN:1999-4915
1999-4915
DOI:10.3390/v11111052