# Infectious Influence: Using fate mapping to determine the impact of viral infection sites on Alzheimer's disease initiation

> **NIH NIH R21** · DUKE UNIVERSITY · 2022 · $201,250

## Abstract

Abstract:
Direct evidence that human olfactory and central nervous system CNS infections play a causal role in AD
remains elusive. The difficulty connecting viruses to AD arises from attempts to detect viral genomes remaining
in AD patient brains, even if immune pressure has long since removed any trace of active viral replication.
Indeed, recent studies have not found evidence for the continued presence of any CNS virus, including herpes
and influenza in the brains of AD patients (3). There is significant evidence that SARS-Cov-2 infects the
olfactory system and can result in neuroinvasion (4), potentially accelerating AD in a rapidly increasing number
of individuals. The common assumption that pathogens render a host acutely ill followed by a return to the
preinfection normalcy, neglects the existence of inflammatory imprinting that drives local and regional changes
in tissue functions even after acute infection is controlled. Infection can permanently remodel chromatin and
alter transcriptional networks of surviving cells. Long lasting infection-dependent transcriptional changes may
contribute to long-term impacts on cellular function and regional/network changes within surrounding cells that
are relevant to host neurological fitness. Rather than focusing on a specific single microbe, our study utilizes
olfactory CNS viral infection models to determine the capacity of seemingly benign infections to specifically
drive long term pathologies. Identifying the long-term functional consequences of infection at the cellular level
requires in vivo lineage tracing. We and others have generated replication competent and pathogenic Cre-
recombinase expressing viruses that specifically label surviving cells following viral clearance. These Cre-
expressing viruses pinpoint the precise anatomical localization of previously infected cells empowering
evaluation of neurodegeneration as a function of proximity to previous infection, as well as allowing
identification of surviving cells fluorescently or through RNA based transcriptomic identification.
While disease associated genetic variants have been identified, and functional alterations shown, the
mechanistic underpinnings of AD initiation are poorly understood, especially given that most AD cases are
sporadic. This proposal seeks to fill gaps in knowledge regarding how viral infection may lead to AD disease:
1) What mechanistic changes caused by viral infection can lead to AD, and 2) are these mechanistic changes
conserved across different types of infections, or are unique pressures applied to achieve a similar outcome.
This lack of detailed understanding regarding the initiation and ongoing pathogenesis behind AD remains a
critical barrier to the development of new treatments. Our proposal will suggest how infection increases
susceptibility among individuals without known familial gene variants.

## Key facts

- **NIH application ID:** 10468164
- **Project number:** 5R21AG074324-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** E. Ashley Moseman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $201,250
- **Award type:** 5
- **Project period:** 2021-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468164

## Citation

> US National Institutes of Health, RePORTER application 10468164, Infectious Influence: Using fate mapping to determine the impact of viral infection sites on Alzheimer's disease initiation (5R21AG074324-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10468164. Licensed CC0.

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