Deciphering Immunopathogenesis of MUCORmycosis to ADVANCE Risk stratification, Diagnosis and Management of the Disease

PROJECT SUMMARY/ABSTRACT Mucorales fungi cause mucormycosis (MCM), a lethal infection in susceptible hosts suffering from diabetic ketoacidosis (DKA), neutropenia, undergoing hematopoietic stem cell or solid organ transplant, or receiving corticosteroids. MCM has poor prognosis, with overall mortality rate of 50% that approaches 100% in certain patient populations. This poor survival is due to limited knowledge about MCM pathogenesis and the immune response to the infection. There is also lack of understanding of the molecular factors that lead to MCM and/or predict response to therapy as well as a paucity of effective assays that can inform early diagnosis and response to antifungal therapy. Importantly, research advances made in the field have largely been slow, and in silo. This Program Project, MUCORmycosis to ADVANCE risk stratification, diagnosis, and management of the disease (MUCOR-ADVANCE), consists of three integrated, complementary projects supported by three cores. The goal of MUCOR-ADVANCE is to decipher the immunopathogenesis of MCM and use this knowledge to develop new diagnostic assays and approach to therapy. MUCOR-ADVANCE is led by world leaders in MCM research, who have collaborated for >20 years in the field. This multidisciplinary proposal will uncover key fungal and host factors that mediate the pathogenesis of MCM and that will be used to as a basis for innovative approaches for early diagnosis of MCM and host- and pathogen-directed adjunctive immunotherapeutic strategies to attenuate Mucorales virulence, reverse immunometabolic defects, and harness physiological immune responses against MCM. Project 1 will delineate the role of unique Mucorales toxins and invasins in the immunopathogenesis of MCM and assess their use as targets for adjunctive immunotherapy and diagnosis. Project 2 will examine the role of metabolic abnormalities in impairing specialized host defense mechanisms against Mucorales with emphasis on immunometabolic strategies focused on free fatty acids and bioactive lipids that mediate the anti- Mucorales activity of phagocytes. Project 3 will use patient samples to identify surrogates of dysfunctional innate effector responses and their prognostic significance in MCM patients and will assess mainly FDA-approved non- cellular immunomodulators (immune checkpoint inhibitors, hematopoietic growth factors, and cytokines) as novel adjunctive therapies in clinically relevant murine models of MCM. All aims will validate the translatability of the in vitro and in vivo models by using specimen prospectively collected by the Clinical Core from MCM patients. The molecular immunopathogenesis studies of MCM will be facilitated by advanced single cell RNA-seq, dual RNAseq and bioinformatic analyses provided by the Genomic/Transcriptomic Core. Finally, an Administrative Core will enable the efficient, cost-effective implementation of the goals of the program. The outcome of the MUCOR-ADVANCE Program project will identify early diagnostic and prognostic biomarkers for improved disease management and introduce novel immune-based adjunctive therapies. These therapies include FDA- approved drugs with the potential to rapidly enhance treatment of this lethal disease.