# Using microbially-experienced mice to study the innate immune response in sepsis

> **NIH VA I01** · MINNEAPOLIS VA  MEDICAL CENTER · 2022 · —

## Abstract

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Early
stages of sepsis are marked by hyperinflammation driven by proinflammatory cytokines (i.e., IL-1β, IL-6, IFNγ,
and TNF). The difficulty in performing hypothesis-driven research in humans justifies the need for a clinically-
relevant, experimental sepsis model. A number of models are commonly used to study the multifactorial
pathophysiology of sepsis, and the dominant mammalian organism used in sepsis research is the mouse (Mus
musculus). While there has been a vast expansion in knowledge regarding the intricate changes that occur
within the immune system following a septic event, virtually all preclinical sepsis research published to date
has relied on the use of mice housed under specific pathogen-free (SPF) conditions. Environmental pathogen
exposure is one important difference between basic human and laboratory mouse biology that must be
considered when using mice to evaluate immune system fitness. Humans are naturally exposed to both
commensal and pathogenic microbes daily from birth, and the immune system of adult humans has been
trained and shaped by each infection and vaccination experienced. While SPF housing of laboratory mice has
been instrumental in increasing experimental reproducibility, it has simultaneously further distanced the mouse
as a model from humans largely because SPF mice live their lives with limited microbial exposure.
This proposal leverages a novel mouse model that mimics a critical aspect of human biology – exposure to
multiple ongoing and resolved infections trains the immune system for robust responses to new pathogens.
Our central hypothesis holds that the exacerbated acute response and mortality seen in septic cohoused
(CoH) mice stems from hyperactivity by peritoneal resident Mf and increased organ dysfunction/damage
stemming from elevated neutrophil responses – largely because of an augmented capacity of these
phagocytes to recognize infection via increased pattern recognition receptor expression. We also posit
microbial exposure via cohousing increases the ‘pathogenicity’ of the gut microbiome, which also contributes to
the increased response by the immune system. In Aim 1, we will define the importance of TLR4 signaling
within peritoneal resident Mf in regulating the magnitude of the acute immune response during sepsis.
Experiments in Aim 2 will define the role played by neutrophils leading to the organ dysfunction/damage and
mortality in septic CoH mice. Finally, studies in Aim 3 will determine how changes in the gut microbiome as
part of the routine treatments for sepsis patients in critical care, including broad-spectrum antibiotics and
interruption of enteral nutrition, lead to the dysfunction of microbiota that increases late sepsis mortality. When
the concepts, preliminary data, and proposed studies in this proposal are considered in sum, this project will
showcase the power of using CoH mice to bet...

## Key facts

- **NIH application ID:** 10367761
- **Project number:** 2I01BX001324-10A1
- **Recipient organization:** MINNEAPOLIS VA  MEDICAL CENTER
- **Principal Investigator:** Thomas S Griffith
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2012-10-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367761

## Citation

> US National Institutes of Health, RePORTER application 10367761, Using microbially-experienced mice to study the innate immune response in sepsis (2I01BX001324-10A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10367761. Licensed CC0.

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