Abstract
Alphaviruses such as Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis virus (EEEV) are arboviruses that can cause severe zoonotic disease in humans. Both VEEV and EEEV are highly infectious when aerosolized and can be used as biological weapons. Vaccines and therapeutics are urgently needed, but efficacy determination requires animal models. The cynomolgus macaque (Macaca fascicularis) provides a relevant model of human disease, but questions remain whether vaccines or therapeutics can mitigate CNS infection or disease in this model. The documentation of alphavirus encephalitis in animals relies on traditional physiological biomarkers and behavioral/neurological observations by veterinary staff; quantitative measurements such as electroencephalography (EEG) and intracranial pressure (ICP) can recapitulate underlying encephalitic processes. We detail a telemetry implantation method suitable for continuous monitoring of both EEG and ICP in awake macaques, as well as methods for collection and analysis of such data. We sought to evaluate whether changes in EEG/ICP suggestive of CNS penetration by virus would be seen after aerosol exposure of naïve macaques to VEEV IC INH9813 or EEEV V105 strains compared to mock-infection in a cohort of twelve adult cynomolgus macaques. Data collection ran continuously from at least four days preceding aerosol exposure and up to 50 days thereafter. EEG signals were processed into frequency spectrum bands (delta: [0.4 - 4Hz); theta: [4 - 8Hz); alpha: [8-12Hz); beta: [12-30] Hz) and assessed for viral encephalitis-associated changes against robust background circadian variation while ICP data was assessed for signal fidelity, circadian variability, and for meaningful differences during encephalitis. Results indicated differences in delta, alpha, and beta band magnitude in infected macaques, disrupted circadian rhythm, and proportional increases in ICP in response to alphavirus infection. This novel enhancement of the cynomolgus macaque model offers utility for timely determination of onset, severity, and resolution of encephalitic disease and for the evaluation of vaccine and therapeutic candidates.
Highlights
The genus Alphavirus of the family Togaviridae composes a group of linear, non-segmented positive-sense single-stranded RNA arboviruses found in many regions of the world
While Venezuelan equine encephalitis virus (VEEV) is only rarely lethal in humans, North American strains of Eastern equine encephalitis virus (EEEV) have a high mortality rate in confirmed cases and a high percentage of survivors have long-term neurological sequelae [3]
There is significant concern that VEEV or EEEV could be employed as biological weapons by rogue nations or terrorists, and these viruses are listed as select agents [7]
Summary
The genus Alphavirus of the family Togaviridae composes a group of linear, non-segmented positive-sense single-stranded RNA arboviruses found in many regions of the world. New World alphaviruses can invade the central nervous system (CNS) and cause severe encephalitis which can be diagnosed by fever, brain swelling, and neurological symptoms such as seizures and a diffuse slowing of brain activity across the physiologically relevant electroencephalography (EEG) frequency spectra [1, 2]. There is significant concern that VEEV or EEEV could be employed as biological weapons by rogue nations or terrorists, and these viruses are listed as select agents [7]. Because of these concerns, there is an urgent need for licensed vaccines and/or treatments
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