Abstract
Aerosol exposure to eastern equine encephalitis virus (EEEV) can trigger a lethal viral encephalitis in cynomolgus macaques which resembles severe human disease. Biomarkers indicative of central nervous system (CNS) infection by the virus and lethal outcome of disease would be useful in evaluating potential medical countermeasures, especially for therapeutic compounds. To meet requirements of the Animal Rule, a better understanding of the pathophysiology of EEEV-mediated disease in cynomolgus macaques is needed. In this study, macaques given a lethal dose of clone-derived EEEV strain V105 developed a fever between 2–3 days post infection (dpi) and succumbed to the disease by 6 dpi. At the peak of the febrile phase, there was a significant increase in the delta electroencephalography (EEG) power band associated with deep sleep as well as a sharp rise in intracranial pressure (ICP). Viremia peaked early after infection and was largely absent by the onset of fever. Granulocytosis and elevated plasma levels of IP-10 were found early after infection. At necropsy, there was a one hundred- to one thousand-fold increase in expression of traumatic brain injury genes (LIF, MMP-9) as well as inflammatory cytokines and chemokines (IFN-γ, IP-10, MCP-1, IL-8, IL-6) in the brain tissues. Phenotypic analysis of leukocytes entering the brain identified cells as primarily lymphoid (T, B, NK cells) with lower levels of infiltrating macrophages and activated microglia. Massive amounts of infectious virus were found in the brains of lethally-infected macaques. While no infectious virus was found in surviving macaques, quantitative PCR did find evidence of viral genomes in the brains of several survivors. These data are consistent with an overwhelming viral infection in the CNS coupled with a tremendous inflammatory response to the infection that may contribute to the disease outcome. Physiological monitoring of EEG and ICP represent novel methods for assessing efficacy of vaccines or therapeutics in the cynomolgus macaque model of EEEV encephalitis.
Highlights
Eastern equine encephalitis virus (EEEV; family Togaviridae; genus alphavirus) is a mosquitotransmitted RNA virus originally named in the 1800’s for the disease it causes in horses
To further characterize the cynomolgus macaque model of EEEV after aerosol exposure, we conducted a detailed analysis of the pathological progression of encephalitis in these animals
Physiological condition of the animals was assessed after infection using electroencephalography (EEG) and intracranial pressure (ICP) along with immunological characterization of the inflammatory cells in the brain
Summary
Eastern equine encephalitis virus (EEEV; family Togaviridae; genus alphavirus) is a mosquitotransmitted RNA virus originally named in the 1800’s for the disease it causes in horses. That the rates of encephalitis caused by EEEV infection in humans may be low, with roughly 2% of adults and 6% of children infected with EEEV developing encephalitis during the course of natural infection [5]. Disease caused by EEEV is preceded by a limited viral prodrome of nausea, vomiting, fever, general malaise, and/or headache that occurs shortly before or coincident with signs of neurological disease [1,2]. Viremia can occur during this viral prodrome, but is thought to decline before signs of neurological disease manifest [6]. Neurological signs of disease correlate with poor patient outcomes, and fulminant CNS disease can have manifestations such as focal cranial nerve deficits, seizures, or coma. As with other encephalitic alphaviruses, EEEV is infectious when aerosolized, and there is concern that EEEV could be used as a biological weapon
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