Impaired glutamate uptake and EAAT2 downregulation in an enterovirus chronically infected human glial cell line.
Rapid and efficient uptake of glutamate via the high-affinity glutamate transporter EAAT2 is important for limiting glutamate-mediated excitotoxicity involved in neuronal death. Furthermore, there is evidence of altered glutamate uptake and catabolism in motor neuron diseases. Such a defect has been reported in amyotrophic lateral sclerosis, the major motor neuron disease, and was associated with impairment in EAAT2 processing. We recently reported the presence of enterovirus genome specifically in the anterior horn of amyotrophic lateral sclerosis cases, suggesting the involvement of a chronic/persistent enterovirus infection in amyotrophic lateral sclerosis. To investigate a putative link between enterovirus infection and the glutamate-mediated excitotoxicity observed in amyotrophic lateral sclerosis, we developed an in vitro model consisting of a human glial cell line infected with ECHOvirus 6, one of the enteroviruses with sequences closely related to those detected in patients with amyotrophic lateral sclerosis. In these glial cells, an ECHOvirus 6 chronic infection was established, resulting in altered extracellular glutamate uptake. This correlated with an aberrant splicing of the EAAT2 pre-messenger ribonucleic acid and a significant loss of EAAT2 protein expression, similar to that observed in patients with amyotrophic lateral sclerosis. These results provide convincing evidence that an enterovirus chronic/persistent infection may alter glial glutamate uptake and catabolism. As enteroviruses are extremely common human pathogens, they may act as a trigger in the development of certain motor neuron diseases, such as amyotrophic lateral sclerosis.
Legay
Vincent
V
UMR 5537, Laboratoire de Virologie Medicale, Domaine Rockefeller, Lyon, France.
Deleage
Christelle
C
Beaulieux
Frederik
F
Giraudon
Pascale
P
Aymard
Michelle
M
Lina
Bruno
B
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D015536:Down-Regulation / Q000502:physiology*; D004770:Enterovirus / Q000254:growth & development; D004769:Enterovirus Infections / Q000378:metabolism; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D009457:Neuroglia / Q000378:metabolism* / Q000821:virology*
D027342:Excitatory Amino Acid Transporter 2; D018698:Glutamic Acid