# Immunometabolism in microbial sepsis

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $285,992

## Abstract

Project Summary/Abstract
Sepsis is the most common cause of mortality in many intensive care units and is responsible for more than
250,000 deaths in the United States annually. Microbial infection and trauma are the most common causes of
sepsis. Sepsis is characterized by an exaggerated innate immune response leading to a cytokine storm.
Recent studies suggest that activation of the innate immune cells causes vigorous metabolic changes towards
increased glucose utilization. Elevated glucose metabolism is also a common feature in the initial state of
sepsis. However, the role of glucose metabolism reprogramming in the regulation of innate immune function
and its relevance to sepsis is poorly understood. In this Proposal, we aim to study the role of two individual
glucose metabolism pathways in microbial sepsis, the hexosamine biosynthesis pathway (HBP) and the
pentose phosphate pathway (PPP). Our preliminary studies revealed essential roles of HBP-associated O-
GlcNAc (O-linked β-N-acetylglucosamine) signaling and PPP in antagonizing inflammatory response and
bacterial spreading, respectively. We further identified nuclear factor E2-related factor-2 (Nrf2) as a critical
mediator of both HBP and PPP pathways. Therefore, promoting the activities of HBP and PPP pathways
through pharmacological activation of Nrf2 may represent a promising therapeutic regimen for treating
microbial sepsis. We hypothesize that 1) HBP-associated O-GlcNAc signaling inhibits the innate immune
activation through O-GlcNAcylation of RIPK3 (receptor-interacting serine/threonine kinase 3); 2) PPP is
required for macrophage bacterial killing and host survival in sepsis by mediating caspase-1 activation; 3)
Genetic and pharmacological activation of these glucose metabolism pathways is effective in the treatment of
microbial sepsis. Cecal ligation and puncture-induced polymicrobial sepsis model will be employed to examine
the role and functions of glucose metabolism pathways. We will test whether dimethyl fumarate (DMF)
treatment plays a protective role in sepsis-induced mortality. The goal of the proposal is to examine the
function and mechanism of two glucose metabolism pathways on macrophage bacterial killing and
inflammation, both of which are key determinants of host survival. Results of these studies will provide novel
insights into the regulation and function of glucose metabolism signaling, which can potentially lead to the
identification of new therapeutic targets in the treatment of microbial sepsis.

## Key facts

- **NIH application ID:** 10190961
- **Project number:** 5R01GM120496-06
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Haitao Wen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $285,992
- **Award type:** 5
- **Project period:** 2017-08-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10190961

## Citation

> US National Institutes of Health, RePORTER application 10190961, Immunometabolism in microbial sepsis (5R01GM120496-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10190961. Licensed CC0.

---

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