# Genomic and molecular determinants of EV-D68 neuroinvasive disease

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $388,750

## Abstract

Virus infections of the central nervous system (CNS) are a significant cause of morbidity and mortality
worldwide. Proven treatments are limited to only a few viruses and even when treatments exist (e.g. acyclovir
for herpes simplex encephalitis) disability and death remain significant. Our knowledge of viral CNS infections,
particularly those involving the spinal cord, is limited and serves as a barrier against the development of novel
treatments for these devastating diseases. Enteroviruses are an important cause of virus-induced CNS
infections. Poliovirus is the most infamous member of the neurotrophic enteroviruses. However, several non-
polio human enteroviruses (NPEVs), including EV-D68, also target the CNS. NPEVs are common, causing an
estimated 10–15 million symptomatic annual infections in the US alone. Although most of these infections do
not result in CNS disease, these viruses can acquire the ability to be neuro-virulent. Recently, large outbreaks of
NPEVs have occurred worldwide that have been associated with neurologic disease and these viruses are
designated “re-emerging pathogens”. For example, in 2014, the United States experienced an epidemic of acute
flaccid myelitis (AFM) cases in children during a nationwide outbreak of previously rare enterovirus D68 (EV-
D68) respiratory disease. Approximately 50% of AFM patients had EV-D68 in respiratory secretions. However,
EV-D68 was not detected in the cerebrospinal fluid of any patient, preventing the establishment of a causative
link between EV-D68 and AFM. We have recently shown that many (including IL/52 and MO/47), but not all
(such as CA4231), clinical isolates of EV-D68 from the 2014 outbreak cause neurologic disease in neonatal mice
and propose to use this novel model of virus-induced CNS disease to define patterns and mechanisms of EV-
D68-induced paralysis. Using chimeric viruses we have demonstrated that the 5’ untranslated region (UTR)
and the viral structural proteins VP3 and VP1 are determinants of paralysis. In the proposed studies we will use
similar methods to determine which viral sequences are involved in specific mechanisms of paralysis, including
neuronal infectivity and apoptosis. An increased knowledge of pathogenic mechanisms that are involved in EV-
D68-induced CNS disease will inform the development of antivirals for EV-D68-induced AFM. In addition, by
focusing our efforts on host responses to EV-D68 infections our experiments may identify therapeutic
strategies that have broad spectrum applicability to additional EVs. Our studies may also have relevance for
other viral and non-viral causes of CNS disease.

## Key facts

- **NIH application ID:** 10867441
- **Project number:** 5R01AI171275-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Kenneth L. Tyler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2023-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10867441

## Citation

> US National Institutes of Health, RePORTER application 10867441, Genomic and molecular determinants of EV-D68 neuroinvasive disease (5R01AI171275-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10867441. Licensed CC0.

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