# IFN responses and SARS-CoV-2 Receptor ACE2 Expression in the airway epithelium of young children with Down Syndrome

> **NIH NIH R01** · CHILDREN'S RESEARCH INSTITUTE · 2020 · $489,740

## Abstract

ABSTRACT
Down syndrome (DS), also known as trisomy 21, is the most common chromosomal abnormality among live-
born infants. DS is associated with a disproportionate high risk for severe viral respiratory infections, a top
cause of mortality in this vulnerable population. Nonetheless, the risk of DS patients to develop severe SARS-
CoV-2 infections during the COVID-19 pandemic has been remarkably understudied. A major concern in DS
individuals the risk to develop hyper-inflammatory responses manifested as cytokine storm and/or multisystem
inflammatory syndrome in children. Indeed, people with DS exhibit hyper-activation of interferon (IFN) signaling
because they have three copies of the chromosome 21, which encodes four of the six IFN receptors.
Importantly, our team and others recently identified that IFNs are strong inducers of the angiotensin-converting
enzyme 2 (ACE2), the cell entry receptor of SARS-CoV-2 in the human airway epithelium. The novel finding
that SARS-CoV-2 may tap into the host IFN-driven airway epithelial antiviral response to enhance its infectivity
represents a paradigm shift for the pathobiology of COVID19, particularly in individuals with DS. The overall
goal of this application is to investigate, for the first time, the airway epithelial IFN-driven antiviral and pro-
inflammatory responses in young children with DS. Our NIH-funded laboratory (R01HL141237) has the
expertise to study the immunobiology of the airway epithelial cell (AEC) of young children, the age group with
the highest risk for severe viral respiratory infections. Our central hypothesis is that the airway epithelium
of DS children exhibits a dysregulated antiviral molecular program leading to enhanced production of
pro-inflammatory cytokines and IFNs (Aim 1); and heightened responsiveness to IFNs leading to
overexpression of ACE2 and increased susceptibility to SARS-CoV-2 infection (Aim 2). Defining the key
innate cytokines/chemokines and the precise molecular pathways dysregulated in the AEC of DS individuals
promises a unique opportunity to discover novel targets to treat severe viral respiratory infections, including
SARS-CoV-2. This new knowledge may have long-lasting impact for people with DS by identifying potentially
novel approaches to prevent severe respiratory infections caused by SARS-CoV-2 and other viruses (e.g.
RSV) in children and adults with DS.

## Key facts

- **NIH application ID:** 10215714
- **Project number:** 3R01HL141237-02S1
- **Recipient organization:** CHILDREN'S RESEARCH INSTITUTE
- **Principal Investigator:** Jyoti K Jaiswal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $489,740
- **Award type:** 3
- **Project period:** 2020-09-11 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215714

## Citation

> US National Institutes of Health, RePORTER application 10215714, IFN responses and SARS-CoV-2 Receptor ACE2 Expression in the airway epithelium of young children with Down Syndrome (3R01HL141237-02S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10215714. Licensed CC0.

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