# Neutrophil-mediated multiple organ dysfunction during sepsis

> **NIH NIH R21** · BOSTON CHILDREN'S HOSPITAL · 2021 · $221,250

## Abstract

Project Summary
Sepsis is the leading cause of death in intensive care unit (ICU) and the most expensive condition treated in
the United States. Over one-third of children who die in tertiary care pediatric ICU (PICU) in the United States
have severe sepsis. Furthermore, recent reports suggest that its prevalence is on the rise. The Sepsis,
Prevalence, Outcomes and Therapies (SPROUT) study, the first world-wide prospective study of pediatric
sepsis showed that the hospital mortality of severe sepsis was significantly high (25%), hinting the immediate
need to improve our care of pediatric sepsis. Given that the mortality of pediatric sepsis is associated with the
presence of multiple organ dysfunction (MODS), it is critical to understand the mechanism of how MODS
develops in pediatric sepsis, which will pave a way for therapeutic intervention. Neutrophils are double-edged
swords in sepsis; they function to eradicate microbes, but also play a significant role in causing MODS in
sepsis. Neutrophils were previously considered homogeneous but a growing literature supports that they form
heterogeneous subpopulations. Our preliminary data in specific pathogen free (SPF) mice with sepsis induced
by cecal ligation and puncture (CLP) model showed the development of organ injury in a time-dependent
manner. In parallel, neutrophils developed heterogeneity by flow cytometry. The immunological profile of SPF
mice is considered representative of immune system in children. Thus this model fits for studying pediatric
sepsis. How neutrophil phenotype correlates with organ injury has not been studied in depth. Here we
hypothesize that 1) neutrophils will show heterogeneous population in pediatric sepsis and there will be the
distinct subpopulation associated with the degree of organ injury during sepsis, and 2) the subpopulation
observed in both septic mice and pediatric patients share common features. We will test these hypotheses in
mice and pediatric patients. Single cell RNA sequencing (scRNAseq) is an extremely robust technology to
delineate population in an unbiased matter and has been increasingly used to define cellular heterogeneity in
immunology field. Understanding the gene signature using scRNAseq will provide us an in-depth knowledge
about neutrophil phenotypes. With dimensional reduction with T-distributed stochastic neighbor embedding,
neutrophil subpopulations (clusters) will be presented. Pathway analysis for each cluster will be performed. We
will determine the correlation between neutrophil subpopulation associated and organ injury in mice and
patients. In addition, we will study in vitro neutrophil functions using blood, and determine their correlation with
neutrophil subpopulations. In mice experiments, we will also perform scRNAseq of neutrophils recruited to liver,
lung and kidney to delineate neutrophil population involved in tissue infiltration. At the completion of this study,
we expect that we identify common neutrophil subpopulation and ...

## Key facts

- **NIH application ID:** 10137983
- **Project number:** 5R21HD099194-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Sophia Koutsogiannaki
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $221,250
- **Award type:** 5
- **Project period:** 2020-04-03 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137983

## Citation

> US National Institutes of Health, RePORTER application 10137983, Neutrophil-mediated multiple organ dysfunction during sepsis (5R21HD099194-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10137983. Licensed CC0.

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