Journal Article

Single-cell analysis of Powassan virus-infected brains reveals age-dependent neuroinflammatory crosstalk and progressive Alzheimer's-like APP/Aβ accumulation

Byrne, Aisling G, Vorkas, Charles K, Chatel-Chaix, Laurent, Gomes, Yago C P, de Souza, Marcos Romario Matos, Kaur, Rimanpreet, Laird, Autumn Y, Finnerty, Catherine E, Mackow, Erich R, Kim, Hwan Keun, Mladinich-Valenti, Megan, Kirillov, Varvara, Lindner, Marissa R, Gorbunova, Elena E, Ikeda, Priscila

2026

Overview

Powassan virus (POWV) causes lethal encephalitis in the elderly and long-term neurological sequelae in survivors. Mirroring human disease, POWV strain LI9 directs age-dependent lethality in C57BL/6 (B6) mice, resulting in spongiform encephalitis, gliosis, and inflammatory cytokine/chemokine responses in the CNS. However, the mechanisms underlying age-dependent lethality and persistent neurodegenerative disease in POWV survivors remain to be resolved. Here, we analyzed cellular CNS responses to POWV LI9 infection in young (10-week-old) and aged (50-week-old) mice using single-cell RNA sequencing. Infection of young mice resulted in inflammatory CNS infiltrates (NK, CD4/CD8 T cells, and monocytes) and interferon responses that coincide with peak viral burden. In contrast, the CNS of aged infected mice instead featured upregulated astrocyte and neuronal genes associated with neurodegenerative and Alzheimer's disease pathways and the transition of homeostatic microglia to a Trem2-ApoE-linked disease-associated microglial transcriptional state. Histological analysis revealed that amyloid precursor protein (APP)/amyloid-β (Aβ) accumulated in the CNS following POWV infection and that POWV envelope protein and APP/Aβ were selectively localized within layers L5/L6 of the cerebral cortex. POWV kinetically increased perinuclear APP/Aβ accumulation during acute infection and was highly expressed in the CNS of POWV survivors. Our findings reveal that POWV triggers glial cell responses and a neurodegenerative disease-associated microglia program of Alzheimer's-like APP/Aβ accumulation in mice, which is consistent with long-term neurological sequelae in human POWV survivors.IMPORTANCEPowassan virus (POWV) causes lethal encephalitis and long-term cognitive deficits in survivors. Using an age-dependent murine model, we reveal that POWV-infected young mice direct robust CNS inflammatory infiltrates associated with viral clearance, whereas aged mice exhibit impaired immune responses and a shift from homeostatic to neurodegenerative glial cell states. POWV prompted the induction of disease-associated microglia (DAM) and Trem2-ApoE axis transcriptional responses that are hallmarks of APP/amyloid-β (Aβ) accumulation in Alzheimer's disease (AD). Remarkably, POWV induced progressive APP/Aβ accumulation in young and aged mice that persisted in survivors after viral clearance. This suggests that POWV induces an APP/Aβ neurodegenerative process and provides a potential cause of long-term neurological sequelae observed in human POWV survivors. Our data suggest that POWV initiates or exacerbates AD-like neuropathology and further rationalizes investigating the role of APP/Aβ responses in other encephalitic viruses.

• Publisher: ASM
• Subject: Cell Biology / Central Nervous System Infections / Clinical Microbiology and Infectious Diseases / Host Cell Response to Viral Infection / Host Immune Response / Host Range and Tropism / Innate Immune Response / Microbial Pathogenesis and Immunology / Neurotropic Viruses / Pathogenesis and Host Response / Research Article / Viral Encephalitis / Viral Manipulation of Host Gene Expression / Viral Pathogenesis / Virology / Virus-Host Interactions