# CNS Senescence and Immunopathology in Lethal POWV Infection of Aged Mice

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2024 · $722,026

## Abstract

Powassan virus (POWV) is a neurovirulent tick-borne flavivirus (FV) emerging in the N.E. US. POWV causes
a 10% fatal encephalitis resulting in severe long-term neurologic damage in 50% of patients. The incidence of
POWV encephalitis in the elderly remains an enigma with mechanisms of POWV neuroinvasion,
neuroinflammation and senescence that contribute to pathology virtually unknown. Mice s.c. inoculated with
POWV LI9 develop lethal neurovirulent disease with overt spongiform brain damage similar to Alzheimer's
disease. Neurovirulence assessed as a function of murine age, revealed POWV LI9 to be lethal in 82% of 50
wk, and 7.8% of 10 wk old C57/Bl6 mice, and consistent with severe POWV neurovirulence in the elderly.
Concomitant with lethality brains of 50 wk old mice revealed higher viral load and cytokine response than 10
wk old mice 15 dpi in addition to microglial activation throughout the CNS, and persistent in survivors. A
passage attenuated LI9-P strain was generated which replicates like LI9 in vitro, but fails to enter the CNS or
cause lethal disease, and protects mice from WT LI9 challenge. This POWV lethal and attenuated POWV pair,
provides a means of defining neurovirulence mechanisms and determinants of POWV entry into the CNS.
 Mechanisms of POWV entry into the CNS remain to be revealed. Initial LI9 and LI9-P comparisons found
that both POWVs productively infect primary human neurovascular barrier cells: brain microvascular
endothelial cells (BMECs) and choroid plexus epithelial cells (CPEpCs). These findings rationalize POWV
entry into the CNS via BBB or BCSFB portals. In contrast to LI9, LI9-P highly induces IFNβ/λ responses in
BMECs and CPEpCs, that may inhibit POWV neuroinvasion. These findings are consistent with mutations in
Envelope and NS3/4A/4B proteins restricting LI9-P neuroinvasion and neurovirulence.
 A POWV reverse genetics system uniquely permits us to modify infectious POWVs. Using LI9/LI9-P
mutants, single cell sequencing, immunohistochemistry, and flow, studies proposed analyze POWV
neuroinvasion, CNS cell tropism and roles for CNS immunopathology and cell senescence as mechanisms of
age-dependent POWV lethality in mice. Temporal scRNAseq analysis of brains, neuroinflammatory responses
and senescent microglial and neuronal progenitor cells (NPCs) will be assessed for roles in POWV directed
spongiform damage and lethality in aged versus young mice. Studies are aimed at revealing age-dependent
differences in CNS regeneration, microglial and T cell responses and POWV clearance from the CNS that
distinguish protective responses of young mice, from lethal POWV infection and long-term CNS damage in
aged mice. Studies are likely to reveal defensive CNS responses, and therapeutic approaches for resolving
viral encephalitis that are applicable to other neurodegenerative diseases of the elderly. Studies proposed
evaluate: 1) Mechanisms of early POWV CNS entry and neuronal depletion; 2) POWV clearance from the CNS
by microglia ...

## Key facts

- **NIH application ID:** 10912176
- **Project number:** 1R01AI183762-01
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Erich R Mackow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $722,026
- **Award type:** 1
- **Project period:** 2024-08-16 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10912176

## Citation

> US National Institutes of Health, RePORTER application 10912176, CNS Senescence and Immunopathology in Lethal POWV Infection of Aged Mice (1R01AI183762-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10912176. Licensed CC0.

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