# The role of Immunoresponsive gene 1 in protection against infection

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2021 · $31,270

## Abstract

PROJECT SUMMARY/ABSTRACT
Hospital acquired infections are a major problem in the United States, affecting approximately 2 million patients
and causing at least 90,000 deaths ever year. New strategies are needed to combat these infections,
especially in light of rising antimicrobial resistance rates among pathogens. Vaccines, one of the most
impactful medical technologies in history, are based on adaptive immunological memory responses, which are
long lasting and antigen specific. It is now known that cells of the innate immune system also can mount
memory responses, but unlike adaptive memory responses, they provide protection against a broad variety of
pathogens. This phenomenon is termed innate immune memory or trained immunity and is a potential solution
for preventing infections in vulnerable populations. The mechanisms behind innate immune memory are not
well understood. Toll-like receptor 4 ligands, including the vaccine adjuvant monophosphoryl lipid A (MPLA),
induce innate immune memory in macrophages. MPLA treatment of macrophages causes metabolic
reprogramming as well as increases antimicrobial functions in vitro. In vivo, it protects against Gram-positive
bacterial, Gram-negative bacterial, and fungal infections. Our preliminary data shows that MPLA treatment
induces high expression of Immunoresponsive gene 1 (Irg1), the enzyme which catalyzes production of
itaconate, leading to improved bacterial clearance, an effect that is reduced in Irg1 knockout mice. Itaconate is
known to alter metabolism through inhibition of succinate dehydrogenase. It is also an antimicrobial metabolite
recently discovered to be delivered to bacteria-containing vacuoles. Based on these findings, we hypothesize
that Irg1 and itaconate enable the generation of innate immune memory by facilitating macrophage
metabolic reprogramming and augmenting lysosome-mediated antimicrobial functions. Aim 1 will
determine the role of Irg1 in generation of the memory phenotype in vitro. Irg1 knockout bone marrow-derived
macrophages (BMDM) will be studied to determine the contribution of Irg1 to the metabolic and functional
changes associated with memory. Treatment with exogenous itaconate will be explored to determine its ability
to induce innate immune memory separately from Irg1 activation. Aim 2 will explore the contributions of Irg1 to
MPLA-induced protection against infection and disease tolerance in vivo. Knowledge of the mechanism of
innate immune memory is critical to its translation to the clinical setting. This project will be undertaken as part
of physician-scientist training through the Vanderbilt MSTP.

## Key facts

- **NIH application ID:** 10310722
- **Project number:** 1F30AI157036-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Margaret Ann McBride
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,270
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310722

## Citation

> US National Institutes of Health, RePORTER application 10310722, The role of Immunoresponsive gene 1 in protection against infection (1F30AI157036-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10310722. Licensed CC0.

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