# Targeting Trained Immunity in Trauma-Induced Immune Dysregulation

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $510,529

## Abstract

PROJECT SUMMARY/ABSTRACT
Traumatic injuries from burns, blasts, or major surgery dysregulates immune system function predisposing the
injured people to life-threatening opportunistic infections or persistent critical illness. Targeted immunotherapies
for traumatic injuries to restore immune system function and homeostasis have not yet been developed and are
urgently needed. The immunophenotypic diversity in humans provides a solid justification to target evolutionarily
conserved innate immunoregulatory networks that are less heterogenous for treatment. As such, the
reprogramming of innate immune cells by a process called “trained immunity” is a promising concept for targeting
therapeutics to reduce the morbidity and mortality from trauma-induced complications. Trained immunity can
occur in short-lived innate immune cells by epigenetically modifying accessibility to immune regulatory genes in
hematopoietic stem cells (HSC), which are then passed on by differentiation to innate effector cells, leaving them
better poised to respond to infection. We have developed Toll-like receptor 9 (TLR9) agonists – unmethylated
CpG-DNA sequences, which are naturally found in bacterial DNA and eukaryotic cell mitochondria - as
immunotherapeutic medical countermeasures to promote immune system recovery after radiation and traumatic
injuries. We recently discovered that mesenchymal stromal cells (MSCs), which are critical cellular residents in
the bone marrow hematopoietic stem cell (HSC) niche, express high TLR9 levels, strongly react to CpG-DNA
stimulation, and mediate emergency granulopoiesis responses to infection in neutropenic mice. This discovery
prompted us to consider trained immunity as a central mechanism contributing to the immune protection from
systemic CpG-DNA treatment in our burn trauma and infection model. Here, we address the hypothesis that
TLR9 agonist therapy mediates protective immunity and restores immune homeostasis by trained immunity
mechanisms involving bone marrow MSCs and HSCs. To test this hypothesis, we propose the following specific
aims: 1) To delineate hematopoietic and peripheral immune consequences of trauma with CpG-DNA therapeutic
intervention, 2) To identify transcriptional and epigenetic changes in bone marrow MSCs and HSCs from injured
and uninjured mice treated with CpG-DNA, and 3) To generate and use chimeric mouse models to delineate
injury and CpG-DNA induced trained immunity phenotypes transferred by HSCs. We anticipate that the results
from this research program will provide pre-clinical mechanistic insights towards translating CpG-DNA as an
immunotherapeutic strategy for trauma-induced immune dysregulation.

## Key facts

- **NIH application ID:** 10861833
- **Project number:** 5R01AI177803-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** JAMES A. LEDERER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $510,529
- **Award type:** 5
- **Project period:** 2023-06-07 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861833

## Citation

> US National Institutes of Health, RePORTER application 10861833, Targeting Trained Immunity in Trauma-Induced Immune Dysregulation (5R01AI177803-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10861833. Licensed CC0.

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