# Project 3 Population studies of major human fungal pathogens: genomic and transcriptomic analyses of interactions with the host and microbiome and the rise of antifungal resistance

> **NIH NIH U19** · BROAD INSTITUTE, INC. · 2021 · $719,433

## Abstract

Fungal pathogens have a major impact on human health; the lack of effective antifungal therapies, the diversity
of species infecting humans, and the emergence of new lineages, species and drug resistance represent major
challenges to treatment. This proposal will examine two species causing the largest number of opportunistic
invasive mycoses and a third species representing a major cause of endemic dimorphic mycoses. We will
compare clinical isolates from each pathogen to determine the genetic basis of highly virulent or antifungal
resistant isolates, and to discriminate how isolates that cause invasive infections differ from those of low virulence
or that are part of a healthy mycoflora. In the first aim, we will study the genetic basis of pathogenesis of
Cryptococcus neoformans, a major cause of infection in immunocompromised individuals, by combining large-
scale phenotyping, whole genome sequencing, and transcriptional analysis of natural isolates. We will
characterize how natural isolates differ in in vivo growth during pulmonary infection and dissemination to the
central nervous system and will use these measures to carry out genome-wide association screens of the
pathogen; in parallel, we will measure the growth of the Cryptococcus gene deletion collection of over 4,000
strains. To highlight changes in gene regulation between isolates and pinpoint genes that are highly expressed
at different infection stages, we will carry out RNA-Seq of in vivo stages and key cells involved in fungal
interactions. We will also examine the microevolution of this pathogen during host infection and compare that to
changes observed in an animal model. In the second aim, we will address a major question about the origin of
bloodstream Candida infections, which are a major cause of mortality in immunocompromised patients. We will
examine the intra-host diversity of Candida isolates between commensal sites in the gut and the skin and isolates
from patients with candidemia to trace the origin of these bloodstream infections. We will adapt new enrichment
approaches to increase the proportion of Candida reads in metagenomic samples. Lastly, we will test isolates
that are more frequently associated with the bloodstream origin to confirm their relative virulence in an animal
model. In aim 3, we will examine isolates of Talaromyces (Penicillium) marneffei collected from patients in a
recent clinical trial comparing two antifungal treatments. This represents the largest collection of clinical isolates
collected for a clinical trial with patient metadata for an endemic mycosis. We will use whole genome and RNA-
Seq analyses to define properties associated with drug resistance and aggressive infections with high mortality.
While these three aims represent independent projects to examine fungal pathogenesis, each utilizes large-scale
‘omics approaches to extend and develop new paradigms for studying and understanding fungal virulence in the
context of natural population ...

## Key facts

- **NIH application ID:** 10163679
- **Project number:** 5U19AI110818-08
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Christina A Cuomo
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $719,433
- **Award type:** 5
- **Project period:** 2014-04-10 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10163679

## Citation

> US National Institutes of Health, RePORTER application 10163679, Project 3 Population studies of major human fungal pathogens: genomic and transcriptomic analyses of interactions with the host and microbiome and the rise of antifungal resistance (5U19AI110818-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10163679. Licensed CC0.

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