Neurological sequelae induced by alphavirus infection of the CNS are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine

Michelle C. Potter, Victoria K. Baxter, Robert W. Mathey, Jesse Alt, Camilo Rojas, Diane Griffin, Barbara Slusher

Research output: Contribution to journalArticle

Abstract

Recovery from encephalomyelitis induced by infection with mosquito-borne alphaviruses is associated with a high risk of lifelong debilitating neurological deficits. Infection of mice with the prototypic alphavirus, Sindbis virus, provides an animal model with which to study disease mechanisms and examine potential therapeutics. Infectious virus is cleared from the brain within a week after infection, but viral RNA is cleared slowly and persists for the life of the animal. However, no studies have examined the effect of infection on neurocognitive function over time. In the present study, we examined neurocognitive function at different phases of infection in 5-week-old C57BL/6 mice intranasally inoculated with Sindbis virus. At the peak of active virus infection, mice demonstrated hyperactivity, decreased anxiety, and marked hippocampal-dependent memory deficits, the latter of which persisted beyond clearance of infectious virus and resolution of clinical signs of disease. Previous studies indicate that neuronal damage during alphavirus encephalomyelitis is primarily due to inflammatory cell infiltration and glutamate excitotoxicity rather than directly by virus infection. Therefore, mice were treated with 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist that can suppress both the immune response and excitotoxicity. Treatment with DON decreased inflammatory cell infiltration and cell death in the hippocampus and partially prevented development of clinical signs and neurocognitive impairment despite the presence of infectious virus and high viral RNA levels. This study presents the first report of neurocognitive sequelae in mice with alphavirus encephalomyelitis and provides a model system for further elucidation of the pathogenesis of virus infection and assessment of potential therapies.

Original languageEnglish (US)
Pages (from-to)159-173
Number of pages15
JournalJournal of NeuroVirology
Volume21
Issue number2
DOIs
StatePublished - Apr 1 2015

Fingerprint

Alphavirus Infections
Diazooxonorleucine
Alphavirus
Glutamine
Encephalomyelitis
Virus Diseases
Sindbis Virus
Infection
Viral RNA
Viruses
Norleucine
Memory Disorders
Culicidae
Inbred C57BL Mouse
Glutamic Acid
Hippocampus
Cell Death
Anxiety
Animal Models
Brain

Keywords

  • 6-Diazo-5-oxo-L-norleucine (DON)
  • Alphavirus
  • Encephalomyelitis
  • Fear conditioning
  • Hippocampus
  • Sindbis virus

ASJC Scopus subject areas

  • Virology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Neurological sequelae induced by alphavirus infection of the CNS are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine. / Potter, Michelle C.; Baxter, Victoria K.; Mathey, Robert W.; Alt, Jesse; Rojas, Camilo; Griffin, Diane; Slusher, Barbara.

In: Journal of NeuroVirology, Vol. 21, No. 2, 01.04.2015, p. 159-173.

Research output: Contribution to journalArticle

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