# Mechanisms of Candida-induced phagolysosome neutralization

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $233,250

## Abstract

Abstract
 Candida albicans is an opportunistic pathogen that is normally maintained in a benign state in non-
sterile body sites by the action of the innate immune system, including phagocytic cells such as macrophages
and neutrophils. When these barriers are compromised, Candida can extend beyond sites of commensal
colonization to cause deep-seated infections. It is now the third most common cause of bloodstream infections
in hospitalized patients and is associated with a 40-50% mortality rate. A model system in which Candida and
macrophages are co-cultured has become a valuable and robust model of host-pathogen interactions capable
of identifying novel virulence attributes of this organism and host strategies for antifungal containment. The
interaction is dynamic, with the fungal cell switching to a filamentous, hyphal, morphology within the
macrophage phagolysosome, neutralizing this ostensibly acidic organelle and, eventually, inducing pyroptosis,
a pro-inflammatory cell death pathway, culminating in the rupture of the macrophage. Two competing, but not
entirely irreconcilable, models exist for how C. albicans disrupts normal phagolysosome integrity. In the first,
proposed by our laboratory and supported by genetic and genomic data, the phagocytosed C. albicans cell
begins catabolizing less preferred carbon sources, including amino acids, carboxylic acids, and N-
acetylglucosamine. A byproduct of this metabolism is the generation of alkaline byproducts that neutralize the
extracellular space, including the lumen of the phagolysosome, thus inducing hyphal growth. The second
model, very recently proposed by Grinstein and colleagues and supported by biochemical data, suggests that
C. albicans cannot out-compete the macrophage machinery that neutralizes the phagolysosome. Rather,
another signal (perhaps CO2) induces hyphal growth and this physically disrupts and neutralizes the
phagolysosome. This proposal includes rigorous and sophisticated cell biological and genetic experiments to
resolve these questions and develop a unified model to explain the Candida-macrophage interaction. We
include tools to assess phagolysosomal pH and integrity via fluorescence microscopy using engineered control
of morphology and metabolism to delinate the temporal course of events that result in fungal escape. Further,
we will test two alternative hypotheses for hyphal induction. The second of these brings together the most
compelling aspects of both models to propose and test a novel mechanism of hyphal induction based on
alkalinization of the C. albicans cytosol. Given the wide adoption of this model system, it is critical that we
understand the fundamental elements of the Candida-macrophage interaction to clarify future goals in this
field.

## Key facts

- **NIH application ID:** 9937668
- **Project number:** 5R21AI147631-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Michael C Lorenz
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $233,250
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9937668

## Citation

> US National Institutes of Health, RePORTER application 9937668, Mechanisms of Candida-induced phagolysosome neutralization (5R21AI147631-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9937668. Licensed CC0.

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