# To Define the Role of C. albicans Candidalysin in the Gastrointestinal Niche

> **NIH NIH R21** · BROWN UNIVERSITY · 2022 · $239,250

## Abstract

Project Summary
 Candida albicans is a pathobiont that colonizes multiple niches in the human body including the
skin, gastrointestinal (GI) tract and urogenital tract. However, this species is also responsible for a variety
of mucosal and systemic infections, with the latter associated with high rates of mortality. In addition to
causing opportunistic disease, fungal colonization of the GI tract is now seen as being critical for education
of multiple aspects of the host immune system. There is therefore a pressing need to understand the
mechanisms underlying C. albicans commensalism and to determine how this fungus modulates host
immune responses.
 In this proposal, we address the role of ECE1 in colonization of the GI tract by C. albicans. The
ECE1 gene product encodes for eight peptides that are generated via Kex2 processing of the full-length
protein. The third Ece1 peptide is now known as Candidalysin – a peptide toxin that directly damages host
epithelial cells and can activate the inflammasome. However, most studies have focused on the role of
ECE1 in in vitro or oral infection models and there is currently limited understanding of whether this gene
impacts C. albicans growth in the GI niche.
 Our preliminary data establishes that ECE1 plays a key role in promoting C. albicans colonization
of the gut. Moreover, the extent to which ECE1 elevates fitness depends on the murine model used, with
the greatest contribution evident in models that retain an intact microbiome (i.e., avoid antibiotic
supplementation). We will build on these observations to determine whether the Candidalysin peptide or
other Ece1 peptide(s) contribute to commensal fitness. Our studies will also address whether Ece1
impacts the bacterial microbiome or host responses to C. albicans, as well as whether Ece1-encoded
peptides promote fungal translocation into the bloodstream and thereby facilitate systemic disease.
 Furthermore, we reveal that a remarkable level of sequence diversity exists between ECE1 alleles
from different C. albicans isolates. We will therefore define ECE1 variation in a diverse collection of clinical
isolates and test whether sequence variation results in functional differences in commensal models. These
experiments will potentially establish a role for ECE1 in determining strain-specific differences in the
species.
 Together, these studies will determine the contribution of ECE1 (and Candidalysin) to the fitness
of C. albicans cells in the commensal GI niche, as well as to the host response to this fungus. We anticipate
that these experiments will expand our understanding of the fungal factors that enable C. albicans
colonization, including the precise role of Ece1 in the biology of this important pathobiont.

## Key facts

- **NIH application ID:** 10495258
- **Project number:** 5R21AI166869-02
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Richard John Bennett
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $239,250
- **Award type:** 5
- **Project period:** 2021-09-24 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495258

## Citation

> US National Institutes of Health, RePORTER application 10495258, To Define the Role of C. albicans Candidalysin in the Gastrointestinal Niche (5R21AI166869-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10495258. Licensed CC0.

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