Development of cellular glues to enhance innate immune responses against fungal pathogens

About This Grant

PROJECT SUMMARY/ABSTRACT Invasive fungal disease is a significant public health concern, causing an estimated 1.5 million deaths yearly. Candida auris is a particularly formidable fungal pathogen due to its high mortality rate and resistance to current antifungal drugs, underscoring the urgent need for new therapies. The traditional antifungal paradigm focuses on developing new small molecules against fungal targets, but this strategy is limited by acquired resistance. As an alternative approach, we propose to develop therapeutic tools that harness the host immune system to combat fungal pathogens. The immune response to fungal pathogens typically involves phagocytic clearance of fungi by innate immune cells, particularly neutrophils. However, as seen in the case of C. auris, some fungal pathogens evade this defense mechanism, thereby sidelining an entire arm of the host’s immune defenses. Thus, we aim to develop “cellular glues”, multivalent ligands that can enhance interactions between fungal and phagocytic cells, to promote immune-mediated pathogen clearance. In Aim 1, we will generate multifunctional compounds that can simultaneously bind to 1) carbohydrate-binding proteins on C. auris and 2) uptake and signaling receptors on phagocytes. In Aim 2, we will assess our compounds’ impact on phagocyte activation by measuring specific immune effector functions. Because our cellular glues are modular, we can establish structure-activity relationships to delineate and optimize the relative effects of our compounds on phagocytosis, oxidative mechanisms, and other immune functions. Finally, In Aim 3, we will determine the impact of the cellular glues on phagocyte-mediated fungal clearance both in vitro and in vivo. We will evaluate the antifungal efficacy of our compounds in co-culture studies with C. auris and phagocytic cells, as well as mouse C. auris infection models. The overall goal of these studies is to determine if our multifunctional ligands can bolster innate immune cell responses against C. auris and serve as novel antifungal agents. We anticipate that this work will produce a fundamentally new and general strategy for directing immune responses against fungal pathogens. The proposed training plan encompasses broad, multidisciplinary training across synthetic chemistry, immunology, and microbiology, which will help advance the applicant’s understanding of antifungal immunity and immunomodulatory materials. A resource-rich training environment coupled with close guidance from a multidisciplinary mentoring team will support the applicant’s development to become a successful physician-scientist leader in infectious diseases.