# Targeting host lipid metabolism to limit tissue damage in necrotizing fasciitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $714,614

## Abstract

ABSTRACT/SUMMARY
Necrotizing Fasciitis (NF) or “flesh-eating disease” is a rapidly progressing bacterial infection with severe
necrosis of the dermis and underlying soft tissues. Treatment of NF requires systemic antibiotics and aggressive
surgical debridement. Even with these treatments, NF has considerable morbidity and mortality. Thus, a better
understanding of the pathophysiology of NF and identification of new treatment strategies to attenuate disease
progression is required. Recent work has revealed that pro-inflammatory signals can increase or decrease
cellular resistance to the cholesterol-dependent cytolysins (CDCs), key microbial toxins that permeabilize cells
and destroy tissues. The induction of a CDC “resistant or sensitive state” for phagocytes was found to be
dependent on the rapid reprogramming of cellular cholesterol homeostasis. Moreover, disrupting the ability of
macrophages to reprogram their lipid metabolic state disrupts the induction of protective states by inflammatory
signals. Thus, an inflammatory-lipid metabolic circuit in host cells serves as a determinant of the pathogenic
potential of CDCs, a major virulence factor in necrotizing skin infections. In this application, we combine
advanced methodologies (e.g., mass spectrometry, single-cell sequencing, and imaging) with genetic and
pharmacologic models of lipid metabolism to understand if tissue lipid metabolism is a host factor that determines
the pathogenic potential of CDCs and group A strep (GAS) infections. Specific Aim 1 will determine the
molecular mechanism underlying how the CH25H-LXR metabolic axis mediates the protection of cells from CDC
toxicity. Specifically, we will pursue our discovery that activation of the LXR signaling pathway profoundly
protects phagocytes from CDC-mediated loss of membrane integrity. Combining lipidomics, transcriptomics,
imaging, and functional assays with gain- and loss-of function models, we will molecularly dissect the lipid
metabolic pathways necessary for LXR-mediated protection from CDC-mediated cytotoxicity. Specific aim 2 will
focus on advancing our understanding of the cell types in the skin necessary and sufficient for LXR-induced
protection from CDC tissue damage. We will apply advanced analytical techniques combined with mouse models
of altered lipid metabolism to determine the cell types and lipid metabolic pathways involved in inducing a
resistant state to CDCs in the skin. Specific Aim 3 determines which host lipid metabolism pathways are critical
for resistance to localized or NF-like experimental GAS skin infection models. Our data shows that dysregulation
of cholesterol metabolism potentiates CDC-mediated tissue damage but activating the LXR pathway induces a
protective state. In this aim, we extend these exciting observations and mechanistically test if modulating lipid
homeostasis in host tissues alters the pathogenesis of experimental NF models and may serve as an adjunct
treatment. We expect that these studies...

## Key facts

- **NIH application ID:** 10639904
- **Project number:** 1R01AI175831-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** STEVEN J BENSINGER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $714,614
- **Award type:** 1
- **Project period:** 2023-02-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10639904

## Citation

> US National Institutes of Health, RePORTER application 10639904, Targeting host lipid metabolism to limit tissue damage in necrotizing fasciitis (1R01AI175831-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10639904. Licensed CC0.

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