C. auris mannosylation genes impact neutrophil evasion

About This Grant

PROJECT SUMMARY Since the identification of the fungal pathogen clinically known as Candida auris in 2009, the incidence of infections caused by C. auris has increased around the world. (This pathogen has recently been reclassified by phylogenomic analysis as Candidozyma auris. Throughout this proposal, I refer to this pathogen as C. auris or Candida auris, the name used clinically.) In fact, between 2019 and 2022, the incidence of clinical C. auris infections reported in the United States increased five-fold. C. auris spreads rapidly within healthcare facilities, particularly critical care units. In addition, C. auris is often drug resistant. Nonetheless, with targeted antifungal therapy, invasive C. auris infection has a crude mortality rate of about 35%. Neutrophils are a crucial defense against many invasive fungal infections, including candidiasis. However, primary human neutrophils exhibit minimal activity against Candida auris in comparison to Candida albicans. There is a critical need to understand immune evasion and, particularly, neutrophil evasion mechanisms for this fungal pathogen with the goal of developing new treatment modalities for invasive infection. This project is focused on identifying neutrophil evasion properties of the C. auris mannans, the polysaccharide chains making up the outermost component of the cell wall. C. auris mannans have been shown to mask β- glucan and chitin, known immunostimulatory motifs in the fungal cell wall. Our lab is interested in defining evasion mechanisms of mannans beyond this masking. We have identified C. auris mannan mutants that are more likely to be engulfed by human neutrophils but do not have increased β-glucan or chitin exposure on the fungal cell surface. I will use these mannosylation mutants of C. auris to define how specific genes impact neutrophil receptor recognition of this pathogen. I will also generate fungal-like mannan-coated particles by binding isolated mannans to functionalized beads and examine mannan-receptor interactions independent of other cell wall components. In addition, I will develop a zebrafish model of invasive C. auris infection following skin disruption. This model will mimic the route of infection seen in hospital settings and allow for in vivo imaging of fungal-neutrophil interactions. The rich academic environment at the University of Wisconsin-Madison offers the medical, scientific, and graduate training resources necessary to actualize the proposed work. The proposal combines the fungal and neutrophil biology expertise of the sponsor and co-sponsor as well as their commitment to training the next generation of physician scientists. Overall, this predoctoral fellowship provides training to achieve the research, clinical, mentorship, leadership, and communication skills necessary to develop as an independent physician scientist investigator.