Abstract
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.
Highlights
Venezuelan equine encephalitis virus (VEEV) is a positive-sense RNA virus (Togaviridae, Alphavirus) that is endemic to Central and South America
Intranasal exposure of C3H/HeN mice to 7000 plaque-forming units (PFU) of 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, but has no effect on overall brain glucose metabolism. This conclusion is supported by the following findings of the current study: (1) whole-brain [18 F]DPA-714 and [18 F]CP-18 uptake increased three-fold; (2) [18 F]albumin uptake increased by approximately 25% across the brain; (3) [18 F]FMISO
Uptake increased by 50% across the whole brain and subregions; (4) whole-brain [18 F]FDG uptake was unaffected by VEEV TC-83 exposure on day 3–10 post infection; (5) [18 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 at day seven, and decreased by day 10, and (c) brain stem and cerebellum continued to rise through day 10
Summary
Venezuelan equine encephalitis virus (VEEV) is a positive-sense RNA virus (Togaviridae, Alphavirus) that is endemic to Central and South America. VEEV is highly pathogenic for equines and humans, leading to significant mortality in equines and high morbidity in humans that can result in fatal encephalitis in ≤1% of cases [1]. VEEV poses a significant threat because of its high infectivity, ease of production, stability, potential for aerosolization, and consistent induction of debilitating disease [2]. The high number of reported cases of laboratory-acquired infections by VEEV highlights the susceptibility of humans to aerosol infection [3]. Despite the significant threat posed by VEEV, no Food and Drug Administration (FDA)-approved medical countermeasures exist to treat this potentially life-threatening infection
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