This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Candida is a clinically important fungal pathogen disproportionately affecting immunocompromised patients. The fungal-immune interface is complex and dynamic, and understanding how this interaction surface changes over time in vivo will require both reductionist and genome-wide interrogation. Focusing on the fungal ligand beta-glucan and its innate immune receptor Dectin-1, this proposal exploits functional genomics tools on both sides of the fungal-host equation and utilizes model organisms to elucidate key modulators of immunity and virulence. Genome-wide screening in fungi will be used to identify evolutionarily conserved fungal gene networks that regulate immune response and are targetable by novel therapeutics. In a complementary way, a top-down unbiased genetic screen in innate immune cells will be utilized along with a bottom-up reconstitution assay to identify immune components that are necessary and sufficient for altering immune recognition and response. Finally, monitoring infection dynamics in vivo will place all of this information in context and fill the current gap in knowledge between in vitro dynamics and survival of experimental infection.
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