# Regulation of neutrophil death by GSDMD in Candida albicans infection

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $442,500

## Abstract

Project Summary
Candida albicans (C. albicans) is a leading cause of bloodstream infection in immunocompromised patients.
Neutrophils play a key role in C. albicans host defense and neutropenia is a major risk factor for developing
severe disseminated candidiasis. In current study, we propose to alleviate neutropenia-related disseminated
C. albicans infection by inhibiting C. albicans-induced neutrophil death and thus enhancing neutrophil-
mediated fungal killing in neutropenic patients. We will do so by targeting Gasdermin D (GSDMD) which has
been implicated in the regulation of neutrophil death. GSDMD was originally identified as a key factor
responsible for the inflammatory form of lytic pyroptotic death (pyroptosis) in macrophages. We recently
reported that GSDMD is also highly expressed in neutrophils and mediates neutrophil death which plays
essential roles in neutrophil homeostasis and resolution of inflammation. Our preliminary data show that C.
albicans can hijack GSDMD-mediated neutrophil death mechanism to eliminate neutrophils and therefore
suppress neutrophil-mediated host defense again C. albicans infection. GSDMD deficiency drastically inhibited
C. albicans-induced neutrophil death and conferred resistance to disseminated C. albicans infection. Together,
these results present a novel pathophysiological role for GSDMD in regulation of neutrophil death, leading us
to hypothesize that inhibition of GSDMD will lead to elevated neutrophil-mediated host defense and should be
a legitimate therapeutic strategy for the treatment of neutropenia-related C. albicans infection. To further
understand the role GSDMD in regulating C. albicans-induced neutrophil death and host fungicidal activity, we
will first reveal the mechanism by which C. albicans activates GSDMD in neutrophils. The contribution of
lysosomal membrane permeabilization (LMP), phagocytosis, ROS, candida hyphae formation, and
candidalysin to GSDMD cleavage will be examined in both human and mouse neutrophils (Aim 1). Next, we
will elucidate the role of GSDMD in regulating neutrophil death in vivo during C. albicans infection in both
normal and neutropenic mice (Aim 2). We will also directly assess the contribution of neutrophil GSDMD to
host defense against C. albicans using a newly developed neutrophil-specific conditional GSDMD KO mouse
(Aim 3). Finally, we will examine whether the host defense against C. albicans can be enhanced by
pharmacologically targeting GSDMD (Aim 4). Together, experiments proposed in these four specific aims will
provide a better understanding of the role and regulation of GSDMD-mediated neutrophil death in
disseminated C. albicans infection. This study will solidify GSDMD and related pathways as novel therapeutic
targets for treatment of neutropenia-related severe candidiasis.

## Key facts

- **NIH application ID:** 10021397
- **Project number:** 5R01AI145274-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Hongbo R Luo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,500
- **Award type:** 5
- **Project period:** 2019-09-20 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021397

## Citation

> US National Institutes of Health, RePORTER application 10021397, Regulation of neutrophil death by GSDMD in Candida albicans infection (5R01AI145274-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10021397. Licensed CC0.

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