# Candida albicans responses to antifungals and cell wall stress

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Candida albicans causes invasive infections like candidemia and intra-abdominal canididiasis (IAC) that are
common among hospitalized patients. The C. albicans cell wall is central to the pathogenesis of candidiasis, but
mechanisms that link cell wall regulation and virulence are only beginning to be understood. Cell wall-active
echinocandin antifungals are front-line agents against invasive candidiasis. However, mortality rates among
patients with candidemia or IAC who are treated with echinocandins are 40% or higher. We have shown that C.
albicans rapidly delocalizes phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2) and septins as part of the natural
response to echinocandins. Targeted disruption of C. albicans INP51, which encodes a PI(4,5)P2-specific 5'-
phosphatase, results in PI(4,5)P2 and septin dysregulation, echinocandin hypersusceptibility, over-activation of
the PKC-Mkc1 cell wall integrity pathway in response to stress, cell wall damage gene expression profiles in
absence of stress, and attenuated virulence during hematogenously disseminated candidiasis (DC) and IAC in
mice. Our data demonstrate that balanced PI(4,5)P2 regulation promotes protective cell wall responses and
virulence through activation of the PKC-Mkc1 pathway, while PI(4,5)P2 dysregulation is associated with
deleterious septin, plasma membrane and cell wall responses. More recently, we established that C. albicans
CAS5, which encodes a major transcription factor downstream of Inp51 and Mkc1, and RIM101, which encodes
a transcription factor induced at pH>5.5, during IAC and in the inp51 mutant, are important determinants of
echinocandin responses and virulence. The objectives of this project are to determine mechanisms by which C.
albicans CAS5 and RIM101 regulate cell wall stress responses and contribute to echinocandin resistance and
the pathogenesis of invasive candidiasis. In aim 1, we will validate genes regulated by C. albicans CAS5 during
IAC as virulence determinants, and identify their biologic functions. Toward these ends, we will use RNA-Seq
to perform transcriptional profiling of cas5 null mutant and CAS5 reconstitution strains in vitro and temporal-
spatially during IAC of mice. Then, we will validate certain Cas5-regulated genes as virulence determinants by
testing mutant strains in the mouse models of IAC and DC, and characterize their functions. In aim 2, we will
use similar approaches to validate genes regulated by RIM101 during IAC as virulence determinants, and identify
their functions. In aim 3, we will identify genes regulated by C. albicans CAS5 and RIM101 in response to
micafungin during IAC, and validate their roles in echinocandin resistance or susceptibility. We will perform
RNA-Seq transcriptional profiling of C. albicans wild-type SC5314, cas5, rim101 and the respective reconstitution
strains in response to micafungin in vitro and during IAC, and validate certain genes as contributing to micafungin
responses in vivo . This project will prov...

## Key facts

- **NIH application ID:** 10412906
- **Project number:** 5I01BX001955-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** CORNELIUS J CLANCY
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-04-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412906

## Citation

> US National Institutes of Health, RePORTER application 10412906, Candida albicans responses to antifungals and cell wall stress (5I01BX001955-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412906. Licensed CC0.

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