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

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 five-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.

Interferon gamma modulation of disease manifestation and the local antibody response to alphavirus encephalomyelitis

“…Carmen et al, 2009;Greene et al, 2008;Nargi-Aizenman & Griffin, 2001;Nargi-Aizenman et al, 2004;Potter et al, 2015).…”

Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis

“…Many cells can produce IL-10, but regulatory T cells play a major role during viral infections of multiple organs, including the CNS (21,(32)(33)(34)(35), and are important determinants of NSV infection outcome in susceptible and resistant strains of mice (20). SINV-induced neurologic disease is a manifestation of the inflammatory response to infection rather than virus replication per se (36)(37)(38). In both NSV-and TE12-induced encephalomyelitis, IL-10 deficiency and more severe disease were associated with fewer Tregs in the CNS than in the CNS of WT mice (19).…”

Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis

“…Likewise, in nonfatal SINV-induced encephalomyelitis, DON treatment reduces neurologic sequelae (Potter et al, 2015). However, neither of these studies included an in-depth examination of the effects of treatment on development of the immune response or on pathologic changes in the CNS during and after treatment.…”

“…During SINV infection, approximately 50% of mice treated with DON develop clinical signs of encephalomyelitis by 7 DPI, compared to almost 100% of untreated, SINV-infected mice (Potter et al, 2015). Because the immune response is almost completely absent in CNS during the period of DON treatment, this suggests another mechanism, such as glutamate excitotoxicity, is contributing to clinical disease development.…”