# Genomic diversity of Candida bloodstream infections

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $219,000

## Abstract

Project Abstract
Candida species are fourth leading cause of bloodstream infections (BSIs) in United States hospitals. BSIs due
to C. albicans and C. glabrata, the most common Candida species to cause invasive infections, are 20%-40%
despite treatment with echinocandins, the frontline antifungal agents. Echinocandin resistance is increasingly
described among C. albicans and C. glabrata clinical isolates. Nevertheless, most echinocandin treatment
failures are not associated with emergence of resistance. Echinocandin tolerance, in which Candida growth is
inhibited but cells remain viable, may predispose to subsequent development of resistance, but clinical relevance
of this phenotype is unclear. The longstanding paradigm is that almost all candidemia and other BSIs stem from
a single, clonal organism. In preliminary studies, however, we showed by whole genome sequencing (WGS)
and phylogenetic analyses that C. albicans and C. glabrata BSIs are caused by mixed populations of genetically
diverse strains, which are not typically recognized by the clinical microbiology laboratory. Upon deeper analysis
of C. albicans WGS data, we found that gene variants identified in multiple patients with BSIs were enriched for
biological processes that are known to be important in echinocandin responses and virulence. Our objectives in
this project are to characterize in greater detail the genetic and phenotypic diversity of bloodstream C. albicans
and C. glabrata strains, with particular attention to strains associated with persistent or recurrent infections
despite echinocandin treatment, and to implicate specific Candida genes and gene variants in echinocandin
tolerance, resistance and virulence. We hypothesize that by studying strains from longitudinal BCs and extra-
blood sites of patients with persistent or recurrent C. albicans or C. glabrata bloodstream infections despite
echinocandin treatment, we will identify novel genes or gene variants that are responsible for echinocandin
tolerance/resistance and virulence. In our first aim, we will complete WGS and analyses of C. albicans and C.
glabrata from baseline BCs (10 patients each). Then, we will perform WGS and analyses of strains from positive
longitudinal blood and extra-blood cultures collected during or after echinocandin treatment. Finally, we will
determine phenotypes of genetically diverse strains from BCs, including echinocandin tolerance and resistance.
In our second aim, we will construct isogenic mutant and complemented C. albicans and C. glabrata strains for
genes and gene variants that are identified and prioritized in aim 1. We will test strains for phenotypes in vitro
and for echinocandin treatment responses and virulence using mouse models of hematogenously disseminated
infections. Results will affirm the extent and type of C. albicans and C. glabrata genetic diversity in BCs, afford
new insights into Candida responses to echinocandins during persistent or recurrent BSIs, and identify novel
gen...

## Key facts

- **NIH application ID:** 10358615
- **Project number:** 5R21AI160098-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** M. Hong Thi NGUYEN
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $219,000
- **Award type:** 5
- **Project period:** 2021-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358615

## Citation

> US National Institutes of Health, RePORTER application 10358615, Genomic diversity of Candida bloodstream infections (5R21AI160098-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10358615. Licensed CC0.

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