My group uses genomic approaches to study human fungal pathogens, with a focus on studying mechanisms of virulence and drug resistance.

The impact of fungal pathogens on global health is significant and increasing, yet current interventions are insufficient to meet this challenge. Genomic approaches provide the best opportunity to examine interactions between different fungal pathogens, their hosts, and associated microbial communities at large scale. My group will take multiple approaches to examine how genome variation of fungal pathogen populations contributes to virulence and host adaptation, understanding antifungal drug resistance, and applying genomic approaches to challenges such as the development of new diagnostics.

 

Mapping the basis of virulence and drug resistance in human fungal pathogens

Cryptococcus neoformans is a fungal pathogen of enormous clinical importance causing life-threatening meningoencephalitis. While Cryptococcus is an opportunistic pathogen, it is clear that some isolates are better adapted to infect humans, possibly due to interactions with other eukaryotes in the environment. Our genome-wide association studies of clinical compared to environmental isolates found that the top associated loci included many genes linked to virulence. Building on this work, my group is characterizing the genetic basis of virulence in clinical collections of C. neoformans using genomic and transcriptomic approaches. We aim to identify genes and pathways that are markers of aggressive isolates, which can be used to guide treatment and select new targets for intervention.

 

Genomic analysis of emerging drug resistance

Antifungal drug resistance in fungi is a rising threat to public health, with wider use of drugs in clinics and cross resistance to those used in agriculture and the appearance of multidrug-resistance species Candida auris raising serious concerns over available treatments.  Our initial genomic analyses of C. auris demonstrated that this outbreak consisted of four geographically specific clades that appear to have emerged nearly simultaneously, and that each clade displayed different sets of mutations contributing to azole resistance. By combining genome-wide association, experimental evolution, and transcriptomic approaches, we seek to explain mechanisms of resistance to the other two major classes of antifungal drugs and to characterize the impact of these mutations on the fungal cell, to better understand how C. auris can tolerate becoming multidrug resistant. This project has supported open, collaborative platforms for genomic analysis, including cloud based pipelines, scripts, and workspaces to enable easy re-use of data and pipelines by the fungal research community.

 

Accelerating fungal diagnostics

Diagnosis of fungal infections in clinical microbiology laboratories is currently a time intensive process that can delay therapeutic decisions. We are adapting an RNA based single molecule detection method originally developed with bacterial species for both the identification of fungal species and typing of antifungal drug resistance. We have demonstrated that this phylogeny-informed rRNA-based strain identification (Phirst-ID) could detect Candida species directly from lysates of blood culture bottles with high specificity and sensitivity. This method was also able to correctly identify clinical cases of mixed Candida species infections. We are extending the approach to target all clinically relevant fungal species. In parallel, for species that display notable drug resistance, we are performing RNA-Seq of drug resistant and sensitive strains to identify markers that can be used to classify drug resistant strains. This is a flexible platform where fungal probes could be combined in a panel with bacterial probes, to allow for a pan-microbial diagnostic in a clinical microbiology setting.

1) NIH 1RO1 AI69066-01

3/6/2023-2/29/2028

Mapping the genomic and molecular mechanisms of antifungal resistance in the emerging fungal pathogen Candida auris

MPI with P. David Rogers (St Jude's Childrens Research Institute)

 

2) NIH 2U19 AI110818-06

4/1/2019-3/31/2024

Major Human Fungal Pathogens: Genomic and Transcriptomic Analyses of Interactions with the Host and Microbiome and the Rise of Antifungal Resistance.

Data Management, Analysis, and Resources Dissemination Core.

PI of Fungal project and Data core of Broad Genomic Center for Infectious Disease (PIs Bruce Birren and Daniel Neafsey)

 

3) NIH  1R01 AI153405-01

7/1/2020-6/30/2025

Rapid fungal identification and antifungal susceptibility testing through quantitative, multiplexed RNA detection.

Collaboration with Roby Bhattacharyya (PI, Broad Institute)

American Academy of Microbiology, Fellow, ASM, 2020-present

Molecular Microbiology and Immunology