# Mechanisms of Immune Dysfunction after Trauma and Surgical Sepsis

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $632,817

## Abstract

Project Summary/Abstract
Trauma and Surgical Sepsis are among the leading causes of morbidity and death worldwide. Both of these
acute insults can lead to immune dysfunction that then contributes to a state of persistent critical illness. This
immune dysfunction is manifested by an excessive systemic inflammatory response that can lead to organ
dysfunction; and a simultaneous suppression of immune defenses that renders patients susceptible to
secondary infections. Our understanding of the mechanisms that activate and propagate these responses is
far from complete. The many failed clinical trials targeting the immune response in sepsis stand as testament
to the importance of understanding the mechanisms that regulate the immune response to trauma and sepsis.
Our strategy utilizes state-of-the-art models and techniques to interrogate the “immunology” of trauma and
sepsis at the mechanistic level. Over the next five years, we will pursue three inter-related strategies. First,
we will translate basic science discoveries into our mechanistic mouse models of sepsis and trauma. We will
focus on aspects of the immune response to trauma and sepsis that overlap between humans and mice.
Fundamental discoveries in the field of immunology are emerging faster than ever before. We will focus
attention on understanding how these discoveries relate to the integrated host immune response to sepsis and
multi-system trauma. Second, we will “reverse translate” discoveries made in critically ill humans (including
those from our own extensive human trauma database and biobank) into our animal models to understand the
mechanistic implications of the observations made in humans. Third, we will test agents that modify promising
therapeutic targets in our models to acquire proof-of-concept insight into the translatability of our mechanistic
research.
Plans for the next 5 years begin with three specific goals. (1) We will establish an integrated view of the role
of endotoxin (LPS) sensing pathways in the immune response to poly-microbial, intra-abdominal sepsis. To do
this we will incorporate recent discoveries on Caspase-11 (Caspase-4/5 in humans), a recently described
intracellular LPS receptor, into studies on the host response to intra-abdominal sepsis. We postulate that High
Mobility Group Box 1 (HMGB1) will play a major role both up- and down-stream of Caspase -11 in sepsis. (2)
We will define the role of the IL-33 - innate lymphocyte cell group 2 (ILC2) axis in the type 2 immune response
that is known to be part of trauma- induced immune dysfunction. We have exciting preliminary data that IL-33
levels correlate with type 2 cytokine levels in humans within the first 24 h after injury. (3) We will test the
efficacy of soluble guanylyl cyclase activation as a target to modify the immune response in sepsis.
Each of these areas of focus represent the “next steps” in our ongoing translational research program. As new
discoveries (including from within our own program) emer...

## Key facts

- **NIH application ID:** 10403953
- **Project number:** 5R35GM127027-05
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** TIMOTHY R BILLIAR
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $632,817
- **Award type:** 5
- **Project period:** 2018-06-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10403953

## Citation

> US National Institutes of Health, RePORTER application 10403953, Mechanisms of Immune Dysfunction after Trauma and Surgical Sepsis (5R35GM127027-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10403953. Licensed CC0.

---

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