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- fever (WNF) and WN neuroinvasive disease (WNND) experience significant long-term cognitive sequelae, including high rates of memory impairment and abnormalities in executive function. While improved survival rates from WNND (~91%) have led to rising numbers of patients currently living with these impairments, few studies have addressed underlying mechanisms responsible for these deficits. To address this, we have developed a new murine model of recovery from intracranial infection with a mutant WNV (WNV-NS5-E218A), leading to uniform infection across CNS regions and measurable spatial learning deficits that persist after viral clearance. Using this model we have traced learning defects to hippocampal pathology including CNS tissue resident memory CD8 T cells (Trm), microglial activation and altered neurogenesis within this brain region. Microarray analyses of differentially expressed mRNAs within the hippocampi of mice with neurocognitive deficits revealed increased expression of a variety of immune molecules expressed by Trm (CD103, CD69, IFITM3), and those known to drive microglial effects on synaptic modeling and neurogenesis (complement proteins C1q and C3), and caspase-1, which drives expression of interleukin(IL)-1. In preliminary studies, Trm are CCR2+IFN-?+ and WNV- recovered IFN-?- and IFN-?R- deficient mice do not display learning defects. Activated microglia and defects in neurogenesis within the subgranular zone (SGZ) of the dentate gyrus, but not the subventricular zone (SVZ), were found to persist long after clearance of replicating virus. Moreover, microglia phagocytosis of synapses was observed to occur via a complement-mediated process. We hypothesize that innate immune responses of hippocampal microglia after WNV infection are driven by Trm and contribute to spatial learning defects via their effects on synaptic elimination and neurogenesis. To test these hypotheses we will 1) Define the role of Trm-derived IFN-? in microglia activation and neurocognitive dysfunction during recovery from WNND, 2) Define the innate immune role of microglia in neural correlates of spatial memory during recovery from WNND; and 2) Determine the role of IL-1R1 signaling in microglial modulation of synapse elimination and neurogenesis in the WNV-recovered CNS.

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. Of these, approximately 45% include WNND (18,746 cases) with <10% mortality (1,668 deaths). Survivors of WNND may continue to exhibit significant neurocognitive deficits that persist for years after clearance of virus. At a >90% rate of survival with ~50% incidence of cognitive disturbance, there are currently approximately 10,000 people living with this sequelae of neuroinvasive WNV infections, with additional cases occurring at rates of 1,000-3,000 per year. Additional encephalitic arboviruses that lead to neuroinvasive disease with neurocognitive sequelae in US patients include St. Louis encephalitis, LaCrosse, Eastern equine encephalitis, and Powassan viruses, with total case numbers in the hundreds20-24. Finally, worldwide, encephalitic arboviruses, including Japanese encephalitis and Rift Valley Fever viruses, cause neurologic illness at the rate of 50- 100,000 cases/year with neurocognitive sequelae in survivors25-27. There are currently no diagnostic or treatment modalities for cognitive sequelae in patients that recover from arbovirus encephalitides. Understanding this process is essential for identifying potential therapeutic targets for the prevention and treatment of debilitating memory disturbances.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052632-12
Application #
9229077
Study Section
Special Emphasis Panel (ZRG1-BDCN-W (02)M)
Program Officer
Wong, May
Project Start
2005-07-20
Project End
2021-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
12
Fiscal Year
2017
Total Cost
$300,234
Indirect Cost
$103,359
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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