Minh-Hong Nguyen, MD, has been awarded funding in the amount of $498,557 for a two-year grant by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) entitled, “Genomic diversity of Candida bloodstream infections.” This proposal was submitted in response to the competitive funding opportunity entitled NIH Exploratory/Developmental Research Grant Program (Parent R21) under funding opportunity number PA-20-195.
Candida species are the fourth leading cause of bloodstream infections (BSIs) in United States hospitals. BSIs due to C. albicans and C. glabrata, the most common Candidaspecies to cause invasive infections, carry mortality rates of 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. The preliminary data for this project, however, suggest that C. albicans and C. glabrata exhibit unrecognized genetic diversity during bloodstream infections.
Dr. Nguyen’s 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. She hypothesizes 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 be able to identify novel genes or gene variants that are responsible for echinocandin tolerance/resistance and virulence.
These findings will challenge current clinical and microbiology laboratory practices, and provide a foundation for studies of genetic diversity during BSIs by other Candida species and bacteria, and mechanisms by which C. albicans and C. glabrata genes promote antifungal tolerance, resistance, and pathogenesis.