Alphavirus Encephalomyelitis: Mechanisms and Approaches to Prevention of Neuronal Damage

Abstract

Mosquito-borne viruses are important causes of death and long-term neurologic disability due to encephalomyelitis. Studies of mice infected with the alphavirus Sindbis virus have shown that outcome is dependent on the age and genetic background of the mouse and virulence of the infecting virus. Agedependent susceptibility reflects the acquisition by neurons of resistance to virus replication and virus-induced cell death with maturation. In mature mice, the populations of neurons most susceptible to infection are in the hippocampus and anterior horn of the spinal cord. Hippocampal infection leads to long-term memory deficits in mice that survive, while motor neuron infection can lead to paralysis and death. Neuronal death is immune-mediated, rather than a direct consequence of virus infection, and associated with entry and differentiation of pathogenic T helper 17 cells in the nervous system. To modulate glutamate excitotoxicity, mice were treated with an N-methyl-D-aspartate receptor antagonist, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists or a glutamine antagonist. The N-methyl-D-aspartate receptor antagonist MK-801 protected hippocampal neurons but not motor neurons, and mice still became paralyzed and died. α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists GYKI-52466 and talampanel protected both hippocampal and motor neurons and prevented paralysis and death. Glutamine antagonist 6-diazo-5-l-norleucine protected hippocampal neurons and improved memory generation in mice surviving infection with an avirulent virus. Surprisingly, in all cases protection was associated with inhibition of the antiviral immune response, reduced entry of inflammatory cells into the central nervous system, and delayed virus clearance, emphasizing the importance of treatment approaches that include prevention of immunopathologic damage.

[18F]DPA-714 PET Imaging Reveals Global Neuroinflammation in Zika Virus-Infected Mice

“…The immune response plays a critical role in the outcome of alphavirus-induced CNS disease as well. Increasing evidence suggest that fatal alphavirus encephaloymyelitis is mediated by the immune response to virus infection rather than direct virus replication (reviewed in [ 34 , 35 ]). Collectively, these results suggest that the use of [ 18 F]DPA-714 PET to measure ZIKV-induced neuroinflammation may provide a more accurate quantification of ZIKV pathology than viral titer measurements alone.…”

Bioinformatics Analysis of Gut Microbiota and CNS Transcriptome in Virus-Induced Acute Myelitis and Chronic Inflammatory Demyelination; Potential Association of Distinct Bacteria With CNS IgA Upregulation

“…Seiichi Omura 1,2 , Fumitaka Sato 1,2 , Ah-Mee Park 1 , Mitsugu Fujita 1 , Sundar Khadka 1 , Yumina Nakamura 1 , Aoshi Katsuki 1 , Kazuto Nishio 3 , Felicity N. E. Gavins 4,5 and Ikuo Tsunoda 1,2 *…”

“…Virus infections can induce tissue damage either by direct virus replication/killing of infected cells (viral pathology) or by immune-mediated tissue damage (immunopathology) (1,2). Virus infections have been associated with acute and chronic inflammatory central nervous system (CNS) diseases, including acute flaccid myelitis (AFM) and multiple sclerosis (MS) (3,4).…”

2016 International meeting of the Global Virus Network

“…Viral persistence and immunemediated clearance are important factors in these sequelae. Griffin described experiments with Sindbis virusda prototype alphavirusdusing a variety of mouse models (Griffin, 2016). Infection of neurons in adult mice resulted in non-fatal encephalomyelitis.…”