# Mechanisms of neutrophil dysfunction in antifungal immunity

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $476,472

## Abstract

ABSTRACT
 Candida albicans is a commensal fungus that resides in the oral cavity and gut mucosa. Normally,
healthy individuals efficiently control C. albicans infection. However, in certain pre-disposing conditions such as
immunosuppression, antibiotic therapy, abdominal surgery, use of invasive medical interventions or kidney
diseases, C. albicans can cause life-threatening disseminated candidiasis (DC). Although hemodialysis is a
major cause of bloodstream infection in patients with kidney disease, mortality due to DC is 2 times higher in
patients with kidney impairment than individuals without renal dysfunction. Thus, kidney disease is a separate
and major risk factor for death from DC in these patients, which has largely been overlooked. It is unknown why
patients with renal ailment are inept to fight DC compared to individuals with normal kidney function. Using a
clinically relevant mouse model of renal disease, we show that mice with kidney dysfunction are far more
susceptible to DC than control animals. Nevertheless, the underlying mechanisms of defect in antifungal
immunity in kidney disease are poorly defined. Interestingly, we have discovered an unanticipated role for
uremia, characterized by the accumulation of uremic toxin(s) in the blood in the absence of kidney function, in
causing neutrophil dysfunction in DC. Our data imply that uremia induces a defect in reactive oxygen species
(ROS) generation by neutrophils, which is essential for the elimination of fungi. In part, we show that this is due
to a defect in glucose transporter1-mediated uptake of glucose by neutrophils, required for glycolytic pathways
upstream of ROS generation. Our hypothesis is that neutrophil-intrinsic impairment in candidacidal function of
neutrophils makes uremic patients more susceptible to death from DC. In Aim 1, we will employ series of in vitro
and in vivo approaches to define the underlying cellular and molecular mechanisms of defect in glucose uptake
and subsequent impairment in ROS production and antifungal activity of neutrophils during uremia. Knowledge
gained from these studies will be utilized to identify potential uremic toxin(s) with neutrophil inhibitory activity.
We will also device novel therapeutic approaches to correct the abnormalities in cell metabolic pathways and
neutrophil dysfunction in kidney diseases. In Aim 2, we will translate and validate our mouse model findings in
patients with kidney disease by collecting biospecimens from pre- and post-hemodialysis patients and compare
antifungal activity of neutrophils to healthy subjects. The goal of this proposal is to define the mechanisms of
defect in antifungal activity of neutrophils in kidney disease and eventually to exploit this information for
therapeutic benefit. Our long-term objective is to reduce the mortality associated with this devastating
nosocomial infection in patients with kidney disease.

## Key facts

- **NIH application ID:** 9990675
- **Project number:** 5R01AI142354-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Partha Sarathi Biswas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $476,472
- **Award type:** 5
- **Project period:** 2019-08-07 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990675

## Citation

> US National Institutes of Health, RePORTER application 9990675, Mechanisms of neutrophil dysfunction in antifungal immunity (5R01AI142354-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9990675. Licensed CC0.

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