# Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity in Down Syndrome

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $388,750

## Abstract

PROJECT SUMMARY
With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human
chromosome 21 (Hsa21), is the most common chromosomal abnormality. While DS is most often recognized for
intellectual disability, congenital malformations, and dysmorphic features, it is also associated with seriously
increased rates and severity of respiratory infection. Indeed, infectious respiratory disease in those with DS
accounts for 54% of hospital admissions and more deaths than any other medical condition. Children with DS
have a 62-fold higher rate of pneumonia than children without DS(1). During the influenza A (H1N1) pandemic
in 2009, 23% of hospitalized patients with DS died vs. only 0.1% of those without DS. Collectively, these data
point to an urgent need to understand how the condition of trisomy 21 contributes to respiratory infectious disease
and to identify potential therapeutic targets. Currently, infectious respiratory disease in DS is commonly attributed
to congenital abnormalities of the nasopharynx and upper and lower airways. However, our preliminary data
support the novel hypothesis that immune cell dysfunction is a primary driver of increased incidence and severity
of infectious respiratory disease in DS. Our data show that the trisomic Dp16 mouse lung has higher levels of
interferons and the immunosuppressive cytokine Interleukin (IL)-10. These changes closely mimic the
dysregulated cytokine response in the human lung that has long been observed following influenza infection,
and is a state linked to increased susceptibility to lethal bacterial pneumonia. Importantly, Dp16 mice are trisomic
for the Hsa21-encoded interferon receptors and interferon-responsive genes. Based on these data, we
hypothesize that the constitutive activation state of interferon signaling and IL-10 signaling in the DS lung drives
immune suppression and predisposes individuals with DS to S. pneumoniae pneumonia. This state phenocopies
the increased susceptibility and severity of S. pneumoniae pneumonia that is observed in non-DS individuals
after a course of viral infection. The high morbidity and mortality associated with infectious respiratory disease
is a seriously neglected area of medical need for people with DS. In addition, chronic lung disease is increasingly
associated with cognitive deficit. Conceptualizing DS as a post-viral state of susceptibility to bacterial infection
challenges the existing paradigm of congenital abnormality. Proposing to understand the mechanisms involved
in immune suppression and to identify therapeutic targets and agents to ameliorate frequency and severity of
disease, while high risk, would, if successful, provide a high payoff in the increased health and longevity of people
with and without DS.

## Key facts

- **NIH application ID:** 9939451
- **Project number:** 5R01AI141662-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MICHAEL E. YEAGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939451

## Citation

> US National Institutes of Health, RePORTER application 9939451, Persistent Post-Viral State of Bacterial Pneumonia Susceptibility and Severity in Down Syndrome (5R01AI141662-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939451. Licensed CC0.

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