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

Mucorales fungi cause mucormycosis (MCM) a lethal infection in susceptible hosts suffering from diabeticketoacidosis (DKA) neutropenia undergoing hematopoietic stem cell or solid organ transplant or receivingcorticosteroids. MCM has poor prognosis with overall mortality rate of 50% that approaches 100% in certainpatient populations. This poor survival is due to limited knowledge about MCM pathogenesis and the immuneresponse to the infection. There is also lack of understanding of the molecular factors that lead to MCM and/orpredict response to therapy as well as a paucity of effective assays that can inform early diagnosis and responseto antifungal therapy. Importantly research advances made in the field have largely been slow and in silo. ThisProgram 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 goalof MUCOR-ADVANCE is to decipher the immunopathogenesis of MCM and use this knowledge to develop newdiagnostic assays and approach to therapy. MUCOR-ADVANCE is led by world leaders in MCM research whohave collaborated for >20 years in the field. This multidisciplinary proposal will uncover key fungal and hostfactors that mediate the pathogenesis of MCM and that will be used to as a basis for innovative approaches forearly diagnosis of MCM and host- and pathogen-directed adjunctive immunotherapeutic strategies to attenuateMucorales virulence reverse immunometabolic defects and harness physiological immune responses againstMCM. Project 1 will delineate the role of unique Mucorales toxins and invasins in the immunopathogenesis ofMCM and assess their use as targets for adjunctive immunotherapy and diagnosis. Project 2 will examine therole of metabolic abnormalities in impairing specialized host defense mechanisms against Mucorales withemphasis 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 innateeffector 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 noveladjunctive therapies in clinically relevant murine models of MCM. All aims will validate the translatability of the invitro and in vivo models by using specimen prospectively collected by the Clinical Core from MCM patients. Themolecular immunopathogenesis studies of MCM will be facilitated by advanced single cell RNA-seq dualRNAseq and bioinformatic analyses provided by the Genomic/Transcriptomic Core. Finally an AdministrativeCore will enable the efficient cost-effective implementation of the goals of the program. The outcome of theMUCOR-ADVANCE Program project will identify early diagnostic and prognostic biomarkers for improveddisease 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.