PROJECT SUMMARY The emerging fungal pathogen Candida auris has produced numerous outbreaks of invasive disease in hospitals worldwide. With mortality rates as high as 60%, the continued rise of this drug-resistant pathogen is alarming. Further understanding of the unexpected virulence of C. auris is desperately needed for the design of innovative therapeutic approaches. My laboratory’s long-term goal is to find new approaches to understand, detect, and treat invasive fungal infections. The objective of this application is to delineate how C. auris evades innate immunity and to develop a novel therapeutic strategy to circumvent this mechanism. We have found that neutrophils, leukocytes critical for control of many invasive fungal infections, fail to kill C. auris. We propose that uncovering the molecular mechanism of this immune evasion will identify new drug targets. Our preliminary data provide compelling evidence for the involvement of a C. auris cell wall component. Furthermore, we have identified a subset of neutrophils with enhanced antifungal activity. We plan to capitalize on this finding to delineate the molecular aspects of a successful neutrophil response against C. auris. This will not only shed light on the virulence of C. auris, but will also establish a platform for future neutrophil-based immunotherapies. We anticipate this approach will have broad implications for the treatment of a variety of drug-resistant or treatment-refractory invasive fungal infections.