# The pathogenesis of enterovirus D68 CNS infection

> **NIH NIH F30** · UNIVERSITY OF COLORADO DENVER · 2021 · $29,575

## Abstract

Project Summary/Abstract
Enterovirus (EV) infections of the central nervous system (CNS) are a significant cause of morbidity and
mortality worldwide. Although polioviruses are among the most well known neurotropic EVs, many non-polio
EVs also cause CNS disease. In 2014, the United States experienced an unprecedented respiratory disease
epidemic of a non-polio EV known as EV-D68. This outbreak was associated with a dramatic rise in the
number of cases of acute flaccid myelitis (AFM), a paralytic condition with striking resemblance to poliomyelitis.
There are currently no approved treatments for AFM. In addition, little is understood about why EV-D68 has
only been recently associated with AFM or about the pathogenesis of AFM. A key barrier to understanding the
pathogenesis of EV-D68 has been a lack of models of EV-D68 CNS infection. We have overcome this
limitation by developing an in vivo model of EV-D68 CNS infection that shares many features with human AFM.
In this model, EV-D68 infects motor neurons resulting in limb paralysis in mice. The viral infection can be
quantified by standard viral titer assays (TCID50) and tracked in motor neurons by immunohistochemistry. In
addition, our preliminary studies have shown that EV-D68 can grow in dissociated mouse motor neuron
cultures. The objective of this proposal is to use these in vivo and in vitro models of EV-D68 CNS infection to
improve our understanding of the viral genetic determinants and pathogenic mechanisms involved in both EV
CNS infection and AFM. Aim 1 will investigate viral genetic determinants of neurovirulence and
neuroinvasiveness using sequencing and molecular cloning techniques, combined with testing in the mouse
model. This aim will allow for understanding of mechanism of infection based on regions of the virus important
for neurovirulence and neuroinvasiveness. Aim 2 will investigate mechanisms of neuroinvasiness and spread
using a microfluidic approach with cultured human induced pluripotent stem cell motor neurons and cortical
neurons. Successful completion will likely provide fundamental knowledge into EV-D68 CNS disease
pathogenesis and has the potential to identify novel therapeutic targets for treating EV CNS disease.

## Key facts

- **NIH application ID:** 10061529
- **Project number:** 5F30AI136403-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Alison Marissa Hixon
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $29,575
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10061529

## Citation

> US National Institutes of Health, RePORTER application 10061529, The pathogenesis of enterovirus D68 CNS infection (5F30AI136403-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10061529. Licensed CC0.

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