# Identifying quantitative trait loci that regulate enterovirus D68 pathogenesis using the Collaborative Cross

> **NIH NIH R21** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $243,000

## Abstract

Project Summary
Enteroviruses are among the most prevalent human pathogens. Traditionally, these viruses were associated
with infection of cells within the alimentary tract, oral-fecal transmission between hosts and the development of
rare neurological complications including acute flaccid myelitis (AFM). Yet, numerous members of this virus
family including human rhinoviruses and enterovirus D-68 (EV-D68) are respiratory pathogens, replicating
within the epithelial cells of the upper and lower respiratory tracts, and transmitted between hosts by aerosols
In 2014 it was recognized that EV-D68 infection can also result in AFM. With each subsequent biennial
outbreak of EV-D68 infection, the number of children infected with EV-D68 has been rising as well as the
number of confirmed cases of AFM. Despite strong epidemiologically evidence that the virus is an etiologic
agent of AFM, this association has been questioned due the inability to isolate infectious virus from the
cerebrospinal fluid of children with EV-D68 induced paralysis. Together, these observations attest to the
socioeconomic impact of EV-D68 infection as well as the unmet medical need for better an understanding of
EV-D68 biology and the development of novel therapeutics. Notwithstanding the development of multiple
animal models of EV-D68 infection, no system replicates the spectrum of pathologies associated with EV-D68;
consequently, these models are insufficient for the development and testing of vaccines and antiviral therapies
to treat or prevent infection or the development of AFM. We hypothesize that the limited genetic diversity of
inbred mice used in many in vivo models of infectious disease limits the establishment of an animal model of
EV-D68 biology. The enhanced genetic diversity of mice of the collaborative cross (CC) emulates that of the
human population as well as the subtleties in associated phenotypes that are missing in null mice. The goal of
the proposed research is to establish a mouse model of EV-D68 pathology and identify naturally-occurring
genetic polymorphisms in loci whose products quantitatively regulate susceptibility to viral disease. To identify
CC mice susceptible to EV-D68 infection, air-liquid interface cultures of the bronchial epithelium and
organotypic brain slice cultures will be generated from 8- and 28-day old mice of randomized genetic
backgrounds and infected with three isolates of EV-D68, and the production of infectious virus will be assessed
by plaque assay. We will also identify the cell types that are infected by, and visualize tissue damage resulting
from, virus infection by H&E staining and indirect immunofluorescence using antibodies generated against the
viral protein VP1, and proteins specific to respiratory and neuronal cell types. The mice identified in Aim 1 in
which EV-D68 replicated with the highest and lowest efficiency will be crossed in Aim 2. Analysis of the F1
generation will determine the mode by which EV-D68 susceptibility is...

## Key facts

- **NIH application ID:** 9958636
- **Project number:** 1R21AI151996-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** VINCENT R RACANIELLO
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $243,000
- **Award type:** 1
- **Project period:** 2020-02-24 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9958636

## Citation

> US National Institutes of Health, RePORTER application 9958636, Identifying quantitative trait loci that regulate enterovirus D68 pathogenesis using the Collaborative Cross (1R21AI151996-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9958636. Licensed CC0.

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