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. Age-dependent 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.

Keywords: AMPA receptor antagonist; Glutamate excitotoxicity; Glutamine antagonist; Immunopathogenesis; Sindbis virus.

Fig. 1

Neuronal maturation leads to restriction of Sindbis virus replication. a Virus replication in the brains of 1-day and 4-week-old mice after intracerebral inoculation [8]. b Virus replication in immature undifferentiated and mature differentiated AP-7 rat neuronal cells [15]

Fig. 2

Effects of treatment of neuroadapted Sindbis virus (NSV)-infected mice with glutamate receptor antagonists. a Survival of NSV-infected mice in the absence of treatment and in the presence of treatment for 7 days with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 or the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist GYKI-52466 [52]. Effects of treatment with AMPA receptor antagonist talampanel on T-cell infiltration into the brain b and on virus replication and clearance from the brain c

Fig. 3

Effect of treatment with 6-diazo-5-oxo-l-norleucine (DON) on hippocampal-dependent memory in Sindbis virus (SINV)-infected mice. Treatment with DON partially inhibited development of abnormalities in contextual fear conditioning 5 days after intranasal infection with SINV [55]