# Dissecting SARS-CoV-2 infection in Down syndrome with congenital heart defects using patient-specific iPSCs

> **NIH NIH R21** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2022 · $234,000

## Abstract

Down syndrome (DS) is the most common genetic disorder occurring in about 1 in 800 live births, and is
characterized by a distinctive facial appearance, intellectual disability, and developmental delays. Gene dosage
imbalance in DS patients, primarily caused by an extra copy of chromosome 21 (trisomy 21), is thought to
contribute to a broad spectrum of coexisting medical conditions. DS is frequently associated with congenital
heart defects (CHDs); approximately 40% of DS patients have some form of CHD, with atrioventricular septal
defects (AVSD) being the most prevalent. The swift global spread of coronavirus disease 2019 (COVID-19)
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the ongoing pandemic.
Intriguingly, DS patients are more vulnerable to SARS-CoV-2 infection: there is a 4-fold increased risk for COVID-
19-related hospitalization and a 10-fold higher risk for COVID-19-related death compared to patients without DS.
Mechanisms by which individuals with DS are more susceptible to COVID-19 are largely unknown. Genetically
engineered mice made trisomic for homologous chromosome 16 (MMU16) were developed to study genotype-
phenotype correlations in DS. However, because authentic SARS-CoV-2 is unable to infect mice due to the
inefficient interaction between the viral S-protein and the mouse orthologue of its receptor, human angiotensin
converting enzyme 2 (ACE2), it is not ideal to recapitulate SARS-CoV-2 infection in DS patients using current
DS mouse models. In this R21 proposal, we aim to bridge this knowledge gap by dissecting the mechanistic
causes of the susceptibility of DS patients to COVID-19 using patient-specific induced pluripotent stem cells
(iPSCs). Some genes encoded by chromosome 21 (e.g. transmembrane proteinase serine 2, TMPRSS2) are
dysregulated in individuals with DS and have been implicated to have a role in SARS-CoV-2 infection. Our central
hypothesis is that upregulation of TMPRSS2 in DS leads to enhanced SARS-CoV-2 infection in the lungs,
resulting in an enhanced cytokine surge that increases the severity of COVID-19. In Specific Aim 1, we will
elucidate the mechanisms underlying the enhanced cytokine surge in Down syndrome in response to SARS-
CoV-2 infection using DS iPSC-derived lung organoids. In Specific Aim 2, we will determine the gene-dosage
effect of TMPRSS2 on SARS-CoV-2 infection in DS iPSC-derived cardiac and endothelial cells. It is expected
that this project will have a major impact on the understanding of susceptibility of DS patients to SARS-CoV-2
infection using clinically relevant and patient-specific cardiac and lung cells.

## Key facts

- **NIH application ID:** 10519313
- **Project number:** 1R21HL165406-01
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Mingtao Zhao
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2022-09-06 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519313

## Citation

> US National Institutes of Health, RePORTER application 10519313, Dissecting SARS-CoV-2 infection in Down syndrome with congenital heart defects using patient-specific iPSCs (1R21HL165406-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10519313. Licensed CC0.

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