Physiological and immunological changes in the brain associated with lethal eastern equine encephalitis virus in macaques

Autor: Tobias Teichert, Theron Gilliland, Joseph R. Albe, William B. Klimstra, Henry Ma, Douglas S. Reed, Devin A. Boyles, Amy L. Hartman, Cynthia M. McMillen, Ivona Pandrea, Jeneveve D. Lundy, Emily L. Cottle, Christina L. Gardner, Matthew D. Dunn, Noah Salama, Aaron W. Walters, Katherine J. O’Malley
Rok vydání: 2021
Předmět:
Male
Eastern equine encephalitis virus
Monkeys
Pathology and Laboratory Medicine
Medical Conditions
0302 clinical medicine
Infectious Diseases of the Nervous System
Biology (General)
Mammals
Innate Immune System
0303 health sciences
Microglia
Eukaryota
Brain
Bioassays and Physiological Analysis
Neurology
Medical Microbiology
Viral Pathogens
Physical Sciences
Cytokines
Macaque
Encephalitis
Primates
Imaging Techniques
QH301-705.5
Alphaviruses
Materials Science
Immunology
Neurophysiology
Viremia
Microbiology
03 medical and health sciences
Signs and Symptoms
biology.animal
Genetics
Microbial Pathogens
Molecular Biology
Organisms
Molecular Development
medicine.disease
Macaca fascicularis
Mixtures
Encephalitis Virus
Eastern Equine
Parasitology
Clinical Medicine
Immunologic diseases. Allergy
Biomarkers
030217 neurology & neurosurgery
Neuroscience
Developmental Biology
Central Nervous System
RNA viruses
Eastern Equine Encephalitis Virus
Chemokine
Physiology
Fevers
medicine.disease_cause
Nervous System
Immune Physiology
Medicine and Health Sciences
Encephalitis
Viral
Materials
Clinical Neurophysiology
Brain Mapping
biology
Electroencephalography
Electrophysiology
Infectious Diseases
medicine.anatomical_structure
Brain Electrophysiology
Vertebrates
Viruses
Female
Anatomy
Pathogens
Research Article
Fever
Neuroimaging
Research and Analysis Methods
Virus
Togaviruses
Virology
Old World monkeys
medicine
Animals
030304 developmental biology
Aerosols
Biology and life sciences
business.industry
Viral encephalitis
Electrophysiological Techniques
RC581-607
Disease Models
Animal
Immune System
Amniotes
biology.protein
business
Zoology
Zdroj: PLoS Pathogens, Vol 17, Iss 2, p e1009308 (2021)
PLoS Pathogens
ISSN: 1553-7374
DOI: 10.1371/journal.ppat.1009308
Popis: 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.
Author summary Eastern equine encephalitis virus (EEEV) is a mosquito-transmitted virus that can cause highly lethal encephalitis in a subset of infected humans. Due to being highly virulent and infectious by aerosol, a need exists to develop vaccines or therapeutics to prevent lethal disease, and FDA approval of such an intervention would likely require use of the FDA’s Animal Rule. 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. We found overwhelming virus infection of the CNS in fatal infections coupled with a strong CNS inflammatory response. Novel findings by EEG and ICP will guide comprehensive studies evaluating the efficacy of medical countermeasures.
Databáze: OpenAIRE
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