Tumor necrosis factor-alpha modulates glutamate transport in the CNS and is a critical determinant of outcome from viral encephalomyelitis.
Neuroadapted Sindbis virus (NSV) is a neuronotropic virus that causes a fulminant encephalomyelitis in susceptible mice due to death of motor neurons in the brain and spinal cord. We and others have found that uninfected motor neurons die in response to NSV infection, at least in part due to disrupted astrocytic glutamate transport, resulting in excitotoxic motor neuron death. Here, we examined the mechanisms of astrocyte dysregulation associated with NSV infection. Treatment of organotypic slice cultures with NSV results in viral replication, cell death, altered astrocyte morphology, and the downregulation of the astrocytic glutamate transporter, GLT-1. We have found that TNF-alpha can mediate GLT-1 downregulation. Furthermore, TNF-alpha deficient mice infected with NSV exhibit neither GLT-1 downregulation nor neuronal death of brainstem and cervical spinal cord motor neurons and have markedly reduced mortality. These findings have implications for disease intervention and therapeutic development for the prevention of CNS damage associated with inflammatory responses.
Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD 21205, USA.
Jessica
J
Carmen
Jeffrey D
JD
Rothstein
Douglas A
DA
Kerr
D018354:Alphavirus Infections / Q000378:metabolism* / Q000821:virology; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000821:virology; D016923:Cell Death; D015536:Down-Regulation; D004679:Encephalomyelitis / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000821:virology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012845:Sindbis Virus / Q000502:physiology*; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D027342:Excitatory Amino Acid Transporter 2; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid