Causes and consequences of gene silencing
Fungal infections in hospitalized patient are among the most difficult to treat and are consequently associated with high mortality rates even with the best available treatments. For over a decade, our laboratory has developed Cryptococcus neoformans as a model system for investigating mechanisms of fungal pathogenesis. This budding yeast is the leading cause of fungal meningitis. Found worldwide in the environment, it preys on highly immunocompromised individuals. As a haploid organism with a complete sexual cycle and facile gene editing, Cryptococcus makes for a great experimental system.
Intracellular Action of An Exported Peptide Drives Virulence
Our laboratory performed the first large scale genetic screens for virulence factors in C. neoformans. These early efforts led to the identification of transcription factor network required for virulence. We have investigated key targets of this network. Through this work, discovered a secreted quorum-sensing peptide produced by Cryptococcus is required for virulence. Remarkably, our analysis indicates that rather than having a cell surface receptor, the peptide must be imported by an oligopeptide transporter, implying an intracellular receptor(s). We are currently searching for the relevant intracellular receptors and investigating the cellular function of this unusual signaling mechanism.
The Cryptococcus Knockout Resource: Opportunity for Discovery
We are nearing completion of multi-year effort to generate a genome-wide knockout collection. This collection is being made available to the research community without restriction through the Fungal Genetic Stock Center (fgsc.net). This resource is accelerating research in our laboratory on virtually all projects. Our short-term goal is to complete the collection, perform quality control analysis, and then perform a series of screens focused on identifying novel virulence mechanisms using unbiased forward genetics. We anticipate that this work will transform our ability to understand how fungal pathogens cause disease.