# Candida albicans regulatory pathways contributing to intra-abdominal candidiasis

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $193,811

## Abstract

Project Summary
Intra-abdominal candidiasis (IAC) is a common, but understudied disease associated with mortality rates of 20%-
40%. Pathogenesis of IAC is poorly understood, in part due to the lack of clinically relevant experimental disease
models. We developed a reproducible mouse model of C. albicans IAC, which recapitulates progression of human
disease from peritonitis to intra-abdominal abscesses (IAAs). Utilizing the model, we have begun to define
pathogenesis mechanisms by identifying relevant C. albicans genes through transcriptional profiling. We have
tested inferences from these studies by characterizing the pathogenicity of select C. albicans gene mutant strains.
Our results show that IAC presents a distinct infection environment compared to other types of IC, as both gene
expression modules and functional pathway relationships differ from those observed in models of candidemia and
invasive kidney infection. The objective of this project is to identify transcriptional regulators, transcriptional
regulator targets, and genetic pathways that serve as virulence determinants during peritonitis and within IAAs.
We demonstrated previously that deletion of C. albicans RIM101, which encodes a transcriptional regulator of
alkaline pH responses, significantly attenuated the course of IAC in mice. Follow-up epistasis tests showed that
Rim101 exerts its virulence effects in part through regulation of SAP5, which encodes a secreted protease. We
hypothesize that a group of transcriptional regulators, including Rim101, govern virulence in IAC, and that novel
infection environments encountered during the disease modulate their functionally relevant target genes. We will
use an unbiased approach to identify IAC-relevant transcriptional regulators, and then pursue a prioritized subset
for dissection of functional pathway relationships. In our first specific aim, we will identify C. albicans
transcriptional regulators that contribute to the pathogenesis of IAC by screening a library of oligonucleotide
signature-tagged, homozygous deletion mutants in our mouse model. Transcriptional regulator mutants that are
significantly attenuated during IAC will be validated as virulence determinants by independently creating null
mutant and complementation strains, and testing them in the mouse model. In the second aim, we will identify
C. albicans transcriptional regulator target genes and genetic pathways that contribute to the pathogenesis of
IAC. We will use RNA-Seq to profile global gene expression by Rim101 and other transcriptional regulator null
mutant and complementation strains temporal-spatially during IAC. Prioritized genes targeted by transcriptional
regulators during IAC will be validated as virulence determinants by testing null mutant and complementation
strains in both peritoneal fluid and IAAs, as well as gene over-expression strains in the transcriptional regulator
null background. Genetic pathways contributing to virulence will be validated by ep...

## Key facts

- **NIH application ID:** 9879685
- **Project number:** 5R21AI144390-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** CORNELIUS J CLANCY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,811
- **Award type:** 5
- **Project period:** 2019-02-22 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9879685

## Citation

> US National Institutes of Health, RePORTER application 9879685, Candida albicans regulatory pathways contributing to intra-abdominal candidiasis (5R21AI144390-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9879685. Licensed CC0.

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