# Targeting ACOD1 to attenuate innate immune responses to lethal infections

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $336,200

## Abstract

ABSTRACT
 A leading cause of microbial infections in hospitalized patients is Gram-negative bacteria, which release the
cell wall component lipopolysaccharide (LPS) capable of activating innate immune pathways. The aconitate
decarboxylase 1 (ACOD1) is an LPS-inducible mitochondrial enzyme that was previously implicated as a
negative innate immune regulator through catalyzing the production of anti-inflammatory itaconate. However, we
recently demonstrated that the LPS-induced ACOD1 up-regulation also confers a robust pro-inflammation
response in monocytes and macrophages in an itaconate-independent manner. Genetic deletion of ACOD1 or
its upstream signaling CDK2 in myeloid cells or pharmacological inhibition of CDK2 (with dinaciclib) uniformly
attenuated infection-induced cytokine storm and animal lethality in pre-clinical setting. Clinically, the CDK2-
ACOD1 axis was similarly up-regulated and positively correlated with the severity of bacterial infections in a
cohort of 40 patients. Thus, our findings have suggested a novel role for ACOD1 in promoting dysregulated
innate immune responses to lethal infections. Our central hypothesis is that ACOD1 exerts pro-inflammatory
action through interacting with other effectors such as GIMAP7. To test this hypothesis, we will exploit a
multifaceted strategy to pursue the following integrated aims. Aim 1: Define the adaptor proteins responsible for
CDK2-mediated ACOD1 upregulation in monocytes and macrophages. Aim 2: Identify the effectors responsible
for ACOD1-mediated pro-inflammatory cytokine production in monocytes and macrophages. Aim 3: Evaluate
the efficacy of anticancer drugs in disrupting ACOD1/GIMAP7 interaction and fighting against lethal infections in
preclinical settings. The completion of these studies will provide new insights into the intricate mechanism
underlying infection-induced innate immune dysfunction and shed light on the development of novel therapeutic
strategy for the management of lethal infections.

## Key facts

- **NIH application ID:** 10894116
- **Project number:** 5R01GM127791-06
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Daolin Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $336,200
- **Award type:** 5
- **Project period:** 2018-08-10 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894116

## Citation

> US National Institutes of Health, RePORTER application 10894116, Targeting ACOD1 to attenuate innate immune responses to lethal infections (5R01GM127791-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10894116. Licensed CC0.

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