Disrupted glutamate transporter expression in the spinal cord with acute flaccid paralysis caused by West Nile virus infection.
Neuroinvasive West Nile virus (WNV) infections may cause acute flaccid paralysis (AFP); in fatal cases, anterior horn cell loss is presumed to be caused by direct viral infection. In related animal models, however, glutamate excitotoxicity mediates bystander injury of uninfected anterior horn cells, suggesting additional pathogenic mechanisms. We examined expression of the principal excitatory amino acid transporter (EAAT) of astrocytes (i.e. EAAT-2 in humans, glutamate transporter 1 in hamsters) in the spinal cord of human WNV-induced AFP patients and in hamsters with WNV-induced AFP by immunohistochemistry. Glial fibrillary acidic protein, synaptic and dendritic markers (i.e. synaptophysin, microtubule-associated protein 2), immune activation (HLA-DR), and viral antigens were also evaluated. Humans and hamsters with WNV-induced AFP had decreased spinal gray matter EAAT expression despite greater numbers of glial fibrillary acidic protein-positive astrocytes compared with controls. Areas of diminished EAAT expression showed reduced synaptic and dendritic protein expression and prominent local inflammation but few infected neurons. These findings suggest that WNV infection results in local immune activation within the spinal cord that in turn causes a failure of astrocyte glutamate reuptake even as the number of astrocytes increases; rising extracellular glutamate levels may then drive excitotoxic injury of both infected and uninfected anterior horn cells. The pathogenesis of this increasingly common disorder likely involves immune response and excitotoxicity mechanisms that are potential therapeutic targets.
Blakely
Pennelope K
PK
Department of Neurology, University of Michigan Medical Center, Ann Arbor, MI 48109-2200, USA.
Kleinschmidt-DeMasters
Bette K
BK
Tyler
Kenneth L
KL
Irani
David N
DN
D000208:Acute Disease; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006224:Cricetinae; D003712:Dendrites / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009187:Myelitis / Q000378:metabolism / Q000473:pathology; D036421:Nerve Fibers, Unmyelinated / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010243:Paralysis / Q000209:etiology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013569:Synapses / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014901:West Nile Fever / Q000150:complications / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; D050491:Glutamate Plasma Membrane Transport Proteins; C493397:SLC1A2 protein, human