# Fungal genomics: population and systematic studies to map determinants of virulence, unique biology, and drug resistance

> **NIH NIH U19** · BROAD INSTITUTE, INC. · 2024 · $2,210,640

## Abstract

Fungal pathogens have an enormous impact on human health; the lack of effective antifungal therapies, the
diversity of species infecting humans, and the emergence of new lineages or species and rising antifungal
resistance represent major challenges to treatment. Clinical isolates display enormous genotypic and
phenotypic variation, yet we lack an understanding of how this variation should impact treatment decisions, as
most studies are performed with laboratory isolates. To interpret variation, we also need to more widely
annotate gene function across the genome. Our long-term goal is to map how pathogen gene content and
variation contributes to infection severity, adaptation, and drug resistance and use this to guide clinical
interventions. This project will use powerful genomic and transcriptomic approaches to examine two species
representing the most severe threats to human health, Cryptococcus neoformans and Candida auris.
In the first aim, we will study the genetic basis of pathogenesis of C. neoformans, a major cause of infection in
immunocompromised individuals, by combining genome-wide association, large-scale phenotyping, and
transcriptional analysis of clinical isolates from two large studies. We will measure survival during pulmonary
infection in mice and will measure virulence attributes of capsule and temperature resistance; these
phenotypes and clinical metadata of infection severity will be utilized for genome-wide association studies. We
will also carry out an analysis of selective constraint to prioritize variants for further analysis. Gene expression
in highly virulent and avirulent isolates will be mapped during pulmonary infection, including profiling
granulomas, and monitoring host transcriptional responses. These analyses will reveal genes associated with
severe disease progression, how variants selected in the population, and will map differences in the host
response for isolates varying in virulence. In the second aim, we will systematically characterize and classify
genes required by the emerging multidrug resistant species Candida auris to respond to antifungal drugs and
to survive in conditions to which it has uniquely adapted including high temperature, high salt, and sweat
media. We will adapt a CRISPRi system for C. auris to enable repression of every gene in the genome and
passage a CRISPRi library to map genes that exhibit growth differences in each condition. In parallel, we will
adapt single-cell RNA-Seq for C. auris and evaluate heterogeneity in the response to antifungal drugs. Finally,
we will passage the CRISPRi library in each condition and perform scRNA-Seq, clustering transcripts from
each perturbation for each condition to develop an atlas of gene expression clusters of C. auris across these
conditions of clinical importance. Our work will provide an unprecedented whole-genome view into these
pathogens, needed to characterize and treat clinical isolates. A synthesis of our findings will guide the
develop...

## Key facts

- **NIH application ID:** 10853973
- **Project number:** 2U19AI110818-11
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Christina A Cuomo
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,210,640
- **Award type:** 2
- **Project period:** 2014-04-10 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853973

## Citation

> US National Institutes of Health, RePORTER application 10853973, Fungal genomics: population and systematic studies to map determinants of virulence, unique biology, and drug resistance (2U19AI110818-11). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10853973. Licensed CC0.

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