This proposal is focused on the pivotal role of astrocytes in molecular mechanisms underlying neurocognitive sequelae of flavivirus encephalitis. WNV is the leading cause of domestically acquired arboviral disease in the United States. In addition to the acute neuroinvasive syndromes and persistent motor deficits, patients that recover from WN neuroinvasive disease (WNND) experience significant long-term cognitive sequelae, including high rates of memory impairment and abnormalities in executive function. We recently established a novel murine model of recovery from intracranial infection with a mutant WNV (WNV-NS5-E218A), which leads to ongoing microglia activation with synapse elimination, decreased adult neurogenesis, and spatial learning defects that persist months after viral clearance These effects on synapses were also observed in patients who succumbed to WNND. While these data provide some molecular explanations for poor spatial learning in WNV-recovered subjects, the mechanisms underlying lack of recovery of the hippocampal circuit are unclear. We recently demonstrated that WNND is associated with T cell-derived interferon(IFN)?, and microglial-derived complement promote elimination of hippocampal CA3 presynaptic terminals, with lack of recovery due to the generation of interleukin(IL)-1?-expressing activated astrocytes. Indeed, inactivation of IL-1R1 signaling in WNV-recovered animals promotes adult neurogenesis, synaptic repair, and prevents defects in spatial learning. These reactive astrocytes also express recently identified markers of neurotoxicity (H2.D1, Gbp2, psmb8), suggesting viral-induced effects on cognition might be perpetuated by the generation of astrocytes with a redirected cell fate. Indeed, increased expression of some of these genes (GFAP, Gpb2, psmb8) is observed in human cortical astrocytes treated with IFN?, also highly expressed within the WNV-infected CNS. Prior research has suggested multiple cellular origins of reactive astrocytes with activated microglia being a potential key player in directing astrogliosis18,19. Similarly, the activation of the inflammasome complex within myeloid cells has been implicated in IL-1? production with IL-1 targeting multiple cell types including neural precursor cells20,21. We hypothesize that macrophage-derived IL-1 directs neuronal precursor cells toward an astrocyte fate during viral encephalitis. We further hypothesize that during recovery, activated microglia promote the differentiation of astrocytes towards neurotoxic phenotypes that inhibit hippocampal repair and recovery from neurocognitive deficits via effects of innate immune cytokines on neural precursor cells (NPC).
Aim 1 : Define the cellular targets of astrocyte-derived, anti-neurogenic cytokines in neurocognitive dysfunction during recovery from flavivirus encephalitis.
Aim 2 : Define innate immune mechanisms that direct and maintain astrogliosis during WNV infection and recovery.
Aim 3 : Define astrocyte-specific responses to IFN? that impact neural correlates of spatial memory during recovery from WNND.

Public Health Relevance

Since WNV arrived in the US in 1999 there have been a total of 41,679 cases of symptomatic WNV infections. Acute symptomatic syndromes include a self-limited febrile illness, West Nile fever (WNF), or more severe neuroinvasive diseases (WNND), including meningitis, encephalitis, or flaccid paralysis. Patients suffering from WNND can experience confusion, fatigue, loss of motor control, memory loss, coma, WITH a mortality rate of only 8-10%. Survivors of WNND may continue to exhibit significant neurocognitive deficits that persist for years after clearance of virus. Studies evaluating the rates of persistent impairment in patients previously diagnosed with WNND report that 40-70% exhibit cognitive symptoms that continue to worsen over time after the episode of acute infection. There are currently no diagnostic or treatment modalities for cognitive sequelae in patients that recover from arbovirus encephalitides, which continue to spread and emerge at an increasing rate.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Wong, May
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Washington University
Saint Louis
United States
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