# Dysfunctional Myelopoiesis and Myeloid-Derived Suppressor Cells in Sepsis Pathobiology

> **NIH NIH RM1** · UNIVERSITY OF FLORIDA · 2022 · $1,685,833

## Abstract

ABSTRACT
Earlier recognition of sepsis and improved implementation of best practices have significantly reduced in-hospital
mortality over the past decade. As in-hospital survival has improved, the number of patients who do not fully
recover has dramatically increased; nearly 50% of surgical sepsis patients will never fully recover and nearly
one-third of these patients will die within 6 months. Currently, one important critical question that vexes medical
practitioners is: why do some surgical sepsis patients rapidly recover while others have poor long-term outcomes
despite our best supportive efforts? Why are some of our comorbid (i.e. cancer, end-stage renal disease, etc.)
populations at increased risk of nonrecovery? Our overarching hypothesis is that the consequences of
surgical sepsis (death and poor quality of life) are the result of an unresolving host leukocyte dyscrasia,
similar to other chronic conditions such as cancer and autoimmune disease. Specifically, the
preferential expansion and self-perpetuation of myeloid-derived suppressor cells (MDSCs), propagated
in part through epigenetic changes in both bone marrow (BM) progenitors and MDSCs, drives non-acute
infectious and noninfectious complications after sepsis. This Program will investigate in human surgical
sepsis the underlying mechanisms that drive ‘dysfunctional myelopoiesis’, expansion of MDSC populations,
suppressed T-cell quantities/function, and the development of patient’s immunosuppressive/inflammatory
endotypes. We will primarily focus on how MDSC expansion evolves over time in surgical sepsis patients who
do or do not rapidly recover; how myelopoiesis is regulated transcriptionally and epigenetically in the bone
marrow of trauma patients who are at high risk of developing sepsis. There are four specific aims: Aim 1. To test
the hypothesis that perpetuation of host MDSCs after acute surgical sepsis drives poor long-term clinical
outcomes in surgical sepsis, including but not limited to increased secondary infections. Aim 2. To test the
hypothesis that failure to recover from surgical sepsis is driven by modifiable epigenetic alterations in circulating
MDSCs that induce and prolong immunosuppressive endotypes. Aim 3. To identify the distinct
immunosuppressive mechanisms of MDSCs from surgical sepsis patients over time, including
immunometabolism, check-point inhibition, reactive oxygen and nitrogen production, and substrate availability.
Aim 4. To test the hypothesis that in response to an initial inflammatory stimulus, the increased risk of developing
surgical sepsis is secondary to immunosuppression driven by a preferential bone marrow hematopoietic stem
cell (HSC) expansion of MDSCs transcriptionally and epigenetically. This will be analyzed in severe blunt trauma
patients at high risk for post-injury sepsis who manifest early changes in bone marrow progenitors and expansion
of immunosuppressive MDSCs. Using the established clinical infrastructure of the Sepsis and Crit...

## Key facts

- **NIH application ID:** 10399985
- **Project number:** 5RM1GM139690-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Philip A Efron
- **Activity code:** RM1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,685,833
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10399985

## Citation

> US National Institutes of Health, RePORTER application 10399985, Dysfunctional Myelopoiesis and Myeloid-Derived Suppressor Cells in Sepsis Pathobiology (5RM1GM139690-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10399985. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*