Cellular Glue Therapeutics 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 and multidrug resistance to small-molecule antifungal agents, underscoring the urgent need for new therapies. As an alternative to the traditional antifungal paradigm, we propose to harness the innate immune system to combat fungal pathogens. The immune response typically involves phagocytic clearance of fungi by innate immune cells, like neutrophils and monocytes. However, as in the case of C. auris, some fungal pathogens evade this defense mechanism. Thus, we aim to develop “cellular glues”, multivalent ligands that enhance interactions between fungal and phagocytic cells to promote pathogen destruction. In the R21 phase, we will determine if cellular glues can enhance fungal elimination by phagocytes. In Aim 1, we will generate multifunctional compounds that can simultaneously bind to glycan-binding proteins on C. auris and uptake and signaling receptors on phagocytes. In Aim 2, we will assess our compound's ability to activate phagocytes and promote phagocyte-mediated killing of C. auris. Because our cellular glues are modular, they are ideal for establishing structure-activity relationships that can be used to delineate and optimize the relative contributions of phagocytosis and other immune effector functions in fungal clearance. The R33 phase will be pursued if our milestones are achieved. In Aim 3, we will determine the safety and efficacy of our cellular glues in vivo. The Mansour and Kiessling Groups will collaborate to assess toxicity, biodistribution, and antifungal efficacy in mouse C. auris infection models. Data from these studies will be further leveraged to improve cellular glue efficacy. Simultaneously, in Aim 4, we will optimize our cellular glues to increase their potency and efficacy based on data from the previous Aims. Specifically, we will exploit our modular synthesis to assemble a set of compounds functionalized with diverse glycan ligands. These can be used to optimize the relative binding affinity for C. auris and the phagocyte receptors to promote the desired responses. The overall goal of these studies is to determine if these multifunctional ligands, which can bolster immune cell responses to C. auris, can serve as novel antifungal agents. We anticipate that a successful demonstration of our approach will yield a fundamentally novel and general strategy for directing immune responses against fungal pathogens.