Trm-Derived IFNg Causes Microglial-Mediated Spatial Learning Defects during Recovery from Differentially Neurotropic Flaviviruses

Identification: Klein, Robyn


Description

Trm-Derived IFNg Causes Microglial-Mediated Spatial Learning Defects during Recovery from Differentially Neurotropic Flaviviruses
 
Charise Garber1, Allison Soung1, Lauren L. Vollmer1, Marlene Kanmogne1, Aisling Last1, Jasmine Brown1, Robyn S. Klein1,2,3
Washington University School of Medicine, Departments of 1Internal Medicine, 2Pathology & Immunology, 3Neuroscience, St. Louis, MO, USA
 
The emerging neurotropic flaviviruses, West Nile and Zika viruses (WNV and ZIKV), differentially target neural cell types during acute encephalitis, however both are associated with post-infectious cognitive sequelae. Using newly established recovery models of viral encephalitis in adult animals, we show that in WNV- and ZIKV-recovered mice, resident memory T cell (Trm)-derived interferon-g (IFNg) signaling in microglia underlies spatial learning defects via virus target-specific mechanisms. WNV, which targets neurons throughout the cortex, has previously been shown to promote microglial-mediated synapse elimination and decreased neurogenesis, the latter of which requires interleukin(IL)-1 signaling. Consistent with this, WNV-recovered animals with deficiency in IFNgR lack upregulation of IL-1 and exhibit repair of synapses. ZIKV, which we show specifically targets the hippocampal formation induces severe spatial learning deficits via microglial IFNgR signaling. However, ZIKV-recovered animals deficient in IFNgR signaling are completely protected from spatial learning defects despite elevated levels of IL-1. These findings suggest cellular target-specific mechanisms of post-infectious cognitive impairments during recovery from encephalitis due to flaviviruses and invoke microglial-mediated responses to Trm-derived IFNg as a unifying mechanism of hippocampal dysfunction in response to neuroinflammation.
 
Funding: NIH/NINDS R01NS052632, NIH/NIAID U19 AI083019

Credits

Credits: None available.

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