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Principal Investigator: Sumant Puri
Organization: TEMPLE UNIV OF THE COMMONWEALTH
Fiscal Year: 2024
Award: $368,909
Funding agency: National Institute of Dental and Craniofacial Research
Candida albicans exists as a commensal yeast in healthy people while it can cause mucosal and systemic
fungal infections including oropharyngeal candidiasis (OPC) in immunocompromised individuals and diabetics.
C. albicans has the ability to sense environmental iron as a signal with the help of its signaling pathways, such
as Mitogen Activated Protein Kinase (MAPK) Cek1, to modulate gene expression in response to extrinsic iron
levels. Recent evidence has shed light on the role of different iron levels between free iron rich gut and free
iron deplete blood, allowing C. albicans to choose between a commensal or virulent lifestyle in these
respective niches. Nothing is known about how variations in iron levels within the oral cavity will influence
virulence during OPC. Our preliminary data shows that iron chelation in murine OPC causes significant
reduction in virulence, while iron supplementation leads to greater fungal load in the tongue tissue of the
infected mice. We also show how iron communicated with various signaling pathways including C. albicans
MAPK Cek1 to modulate the fungal cell wall (CW), thereby affecting response to antifungals (by changing CW
component levels) and host immune attack (by affecting exposure of immunogenic β-glucan in the CW). The
main goal of this project is to understand the mechanisms behind iron-mediated changes in C. albicans CW
that in turn effect the outcome of infection during OPC. Besides, in vitro experiments to address this goal, we
will use our murine OPC model and mice will be repleted or depleted in systemic iron levels with iron
supplementation (with iron dextran) and iron chelation (with iron chelator Deferasirox), respectively. We will
also study mucosal colonization by C. albicans in Caenorhabditis elegans worms with human-like iron
disorders, to evaluate fitness of fungal virulence traits directly in host with varying iron levels. Our overall
hypothesis is that iron communicates with various signaling pathways to modulate fungal CW, in turn affecting
hyphal morphogenesis, drug sensitivity, and susceptibility to host immune response, in OPC. We will test our
hypothesis using three specific aims: 1) Define iron-induced signaling mechanisms that modulate C. albicans
β-glucan exposure, levels of CW components, and hyphal morphogenesis, 2) Determine how iron affects C.
albicans CW remodeling and hyphal morphogenesis during murine OPC to impact antifungal drug
susceptibility, and 3) Evaluate how changes in host iron levels modulate innate immune defense mechanisms
against C. albicans in vitro, during murine OPC, and in C. elegans. This work will provide insights into how
varying iron levels in susceptible populations will affect the outcome of C. albicans infection during OPC.
Terms: <Address><Affect><Architecture><Autoregulation><Blood><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Body Tissues><Buccal Cavity><Buccal Cavity Head and Neck><C albicans><C auris><C elegans><C. albicans><C. auris><C. elegans><C. glabrata><C.albicans><C.elegans><Caenorhabditis elegans><Candida><Candida albicans><Candida auris><Candida glabrata><Cavitas Oris><Cell Body><Cell Communication and Signaling><Cell Mediated Immunology><Cell Signaling><Cell Wall><Cell-Mediated Immunity><Cells><Cellular Immunity><Chitin><Chromatin><Communication><DCT1><DMT1><Data><Defense Mechanisms><Divalent Cation Transporter 1><Drug resistance><Drugs><Engineering / Architecture><Environment><Fe chelation><Fe element><Fe supplementation><Ferridextran><Fungus Diseases><Gene Expression><Generalized Growth><Genes><Glucans><Glucose Polymer><Goals><Growth><Homeostasis><Human><Hyphae><Immune><Immune response><Immune system><Immunes><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunological response><Immunosuppressed Host><In Vitro><Individual><Infection><Intracellular Communication and Signaling><Iron><Iron Chelates><Iron Chelating Agents><Iron Chelation><Iron Metabolism Disorders><Iron chelator><Iron dextran><Iron-Dextran Complex><Life Style><Lifestyle><Link><MAP kinase><Macrophage><Mannan><Mannans><Marrow Neutrophil><Measures><Mediating><Medication><Mice><Mice Mammals><Microbial Biofilms><Mitogen-Activated Protein Kinases><Modeling><Modern Man><Monilia><Morbidity><Morbidity - disease rate><Morphogenesis><Mouth><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mycoses><Mφ><NRAMP2><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nutritional Immunity><Oral><Oral Moniliasis><Oral candidiasis><Oral cavity><Oropharyngeal Candidiasis><Outcome><Pathogenesis><Pattern><Persons><Phagocytes><Phagocytic Cell><Phagocytosis><Pharmaceutical Preparations><Physiological Homeostasis><Play><Polyglucoses><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Predisposition><Production><Property><Repression><Role><SLC11A2><SLC11A2 gene><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Structure><Susceptibility><Testing><Therapeutic Fungicides><Thrush><Tissue Growth><Tissues><Tongue><Torulopsis glabrata><Transcription Regulation><Transcription Repressor><Transcriptional Control><Transcriptional Regulation><Transcriptional Repressor><Variant><Variation><Virulence><Virulent><Work><Yeasts><amebocyte><anti-fungal><anti-fungal agents><anti-fungal drug><anti-microbial><antimicrobial><beta-Glucans><biofilm><biological signal transduction><cytokine><diabetic><divalent metal transporter-1><drug resistant><drug sensitivity><drug/agent><experiment><experimental research><experimental study><experiments><extracellular><fitness><fungal infection><fungus><fungus infection><genetic repressor><host response><immune system response><immunogenic><immunoresponse><immunosuppressed patient><in vivo><innate immune mechanisms><insight><iron disorder><iron supplementation><microbial colonization><morphogenetic process><mortality><mouth candida><mycotic stomatitis><natural resistance-associated-macrophage protein 2><neutrophil><novel><ontogeny><oral candida><oropharyngeal thrush><pathogen><psychological defense mechanism><recruit><resistance to Drug><resistant to Drug><response><social role><solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2><synergism><trait><translation strategy><translational approach><translational strategy><treatment strategy><β-Glucans>