# Host genetic determinants of neuroinvasive flavivirus pathogenesis

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $67,582

## Abstract

PROJECT SUMMARY
Powassan virus (POWV) is an emerging tick-borne neuroinvasive flavivirus. Similar to mosquito-borne
flaviviruses such as West Nile virus and Japanese encephalitis virus, POWV causes neuroinvasive disease,
including encephalitis, meningitis, paralysis, and death. While the majority of flavivirus infections result in
asymptomatic infection, a subset of symptomatic flavivirus infections progress to neuroinvasive disease,
although the factors influencing susceptibility to severe disease are not fully understood and little is known about
the pathogenic mechanisms of POWV. We hypothesize that variation in host antiviral response genes
contributes to differential disease outcome following flavivirus infection. We propose to use Collaborative Cross
(CC) mice to characterize features of POWV pathogenesis and identify host genes that contribute to POWV
susceptibility. The CC is a mouse genetic reference population of recombinant inbred mice generated by
crossing eight founder lines that represent three wild-derived and five classical laboratory mouse lines. The CC
captures the genetic diversity of laboratory mice in a reproducible manner, since each of the ~80 lines has a
known and fixed genome, providing a valuable tool for mapping complex traits. In preliminary studies, we infected
a panel of Oas1b-null CC mouse lines with POWV and observed a range of susceptibility phenotypes, suggesting
there are host factors other than the well-characterized flavivirus restriction factor Oas1b that modulate POWV
pathogenesis in mice. We identified multiple highly susceptible lines (100% lethality), including CC071, and a
single resistant line (0% lethality), CC045. Building on this preliminary data, we propose to i) determine viral and
immunologic features of POWV pathogenesis in susceptible and resistant CC lines, and ii) map Quantitative
Trait Loci (QTL) associated with POWV pathogenesis using F2 progeny of susceptible and resistant lines. In
Aim 1, we will evaluate viral loads and infiltrating leukocytes in the CNS following POWV infection, characterize
POWV replication in primary cells, and assess blood-brain barrier permeability, using susceptible (CC071) and
resistant (CC045) CC lines. In Aim 2, we will evaluate POWV lethality, viral loads, and infiltrating leukocytes in
the CNS of F2 mice and map QTL associated with these phenotypes to identify host genetic elements that
contribute to POWV susceptibility. The proposed studies will further our understanding of flavivirus neuroinvasive
disease through identification of host genetic factors that modulate POWV susceptibility in mice and provide
insights into factors that impact neuroinvasive flaviviruses more broadly. The proposed training plan will focus
on building a foundation in quantitative genetics techniques to investigate viral and immunologic mechanisms of
POWV pathogenesis, and will prepare me for a career as an independent investigator using quantitative genetics
techniques to study infec...

## Key facts

- **NIH application ID:** 10387019
- **Project number:** 1F32AI161786-01A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** BRITTANY JASPERSE
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $67,582
- **Award type:** 1
- **Project period:** 2022-03-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387019

## Citation

> US National Institutes of Health, RePORTER application 10387019, Host genetic determinants of neuroinvasive flavivirus pathogenesis (1F32AI161786-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10387019. Licensed CC0.

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