Background

The ecological roles occupied by fungal colonizers of the gastrointestinal tract and their contributions during bacterial infections are virtually unknown. Clostridioides difficile is a spore-forming, anaerobic, bacterial pathogen capable of inflicting severe damage to the human gastrointestinal (GI) tract by producing toxins. C. difficile is responsible for nearly half a million cases yearly with ~30,000 fatalities. Treatment for C. difficile infection (CDI) adds a significant cost to the already strained healthcare system (~$4.8 billion). C. difficile is highly dependent on the host GI microbiota and as such, antibiotic treatment is a key predisposing factor. Antibiotic treatment also expands fungal populations, commonly Candida species, in the GI tract of patients and murine models setting the stage for transkingdom interactions. Markey et al., recently showed that GI colonization with C. albicans protects mice from lethal CDI. We recently showed that colonization with Nakaseomyces glabratus (formerly Candida glabrata) significantly exacerbates CDI by enhancing C. difficile burden and toxin production. Moreover, C. difficile and N. glabratus form robust polymicrobial biofilms in vitro, a mechanism with potential to impact CDI relapse. To date, the role of transkingdom interactions during CDI and their impact on disease progression and outcome has been ignored. CDI is a complex disease further complicated by the development of drug resistance and relapse. Defining the molecular mechanisms that underpin transkingdom interactions will identify novel biology that will unlock aspects of CDI not previously explored. By ignoring the fungal component during bacterial infections such as CDI, we narrow the landscape of therapeutic targets.

Our long-term goal is to define mechanisms by which GI bacterial pathogens such as C. difficile interact with fungal colonizers like N. glabratus and how these interactions impact host health.

Projects areas in the lab include:
1. Defining N. glabratus-C. difficile molecular mechanism(s) required for transkingdom interactions.
2. Characterization of the host immune response during N. glabratus colonization and CDI.
3. Determining the role of key genes in N. glabratus biology as it relates to polymicrobial interactions and gastrointestinal colonization.
4. Identification of the molecular mechanism(s) of action for a small molecule inhibitor of Candida albicans filamentation and biofilm formation.
5. Defining the mechanisms utilized by N. glabratus for colonization of distinct gastrointestinal niches.
6. Identification of repositionable drugs to target C. difficile biofilms with the goal of preventing disease relapse.
7. Identification of repositionable drugs to target N. glabratus planktonic and biofilm lifestyles.
8. Characterizing fungal biology in anaerobic environments.

Projects are available in all areas!