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Principal Investigator: James B Konopka
Organization: STATE UNIVERSITY NEW YORK STONY BROOK
Fiscal Year: 2024
Award: $528,804
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The human fungal pathogen Candida albicans is a leading cause of hospital-acquired bloodstream
infections and can disseminate to become lethal. There is an urgent need to improve the therapeutic
management of C. albicans infections, since current antifungal drugs have limited effectiveness and
drug-resistant strains are emerging. The pathogenic effects of C. albicans are caused by its ability to
grow in the host and disseminate to internal organs. The plasma membrane is fundamentally important
for these processes, as this essential barrier mediates a wide range of functions that are critical for
virulence including cell wall synthesis, secretion of virulence factors, morphogenesis, and nutrient
uptake. The importance of the plasma membrane is highlighted by the fact that it is the target for most of
the currently used antifungal drugs and many antimicrobial peptides. Therefore, a better understanding
of plasma membrane organization and function is needed to facilitate the design of new therapeutic
treatments and to increase the effectiveness of current antifungal drugs. To address this gap in
knowledge, the Aims are designed to take advantage of recent discoveries to identify novel mechanisms
by which the plasma membrane protects C. albicans from stressful conditions in the host. Aim 1 is to
define the mechanisms that protect the plasma membrane against the oxidative burst in the host, which
can cause a chain reaction of lipid peroxidation that destroys membrane integrity. These studies will
leverage our recent identification of a new pathway that protects C. albicans against lipid peroxidation.
Aim 2 will define how the PM resists stress caused by HOCl (hypochlorous acid; bleach) that is produced
by myeloperoxidase during the neutrophil oxidative burst. Although neutrophils are well known to
produce HOCl, little is known about its effects on the plasma membrane or how C. albicans protects
against it. Aim 3 is to define how the C. albicans PM plays a key role in resisting copper and cell wall
stress, which are also encountered in the phagosome. This aim takes advantage of our discovery that
specialized plasma membrane subdomains known as eisosomes or MCC domains promote proper PM
architecture needed for resistance to copper and cell wall stress. Defining how the C. albicans plasma
membrane resists stress is expected to reveal novel mechanisms of pathogenesis that will aid future
studies in development of new therapeutic approaches and increase our understanding of current
antifungal drugs to improve the prospects for their more effective use.
Terms: <Address><Amphotericin><Antioxidants><Architecture><Azoles><Baker's Yeast><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Brewer's Yeast><C albicans><C. albicans><C.albicans><Candida albicans><Cell Body><Cell Membrane Lipids><Cell Wall><Cell membrane><Cells><Cellular biology><Cellular injury><Chemicals><Copper><Cu element><Cytoplasmic Membrane><Data><Development><Drug resistance><Effectiveness><Engineering / Architecture><Environment><Fatty Acid Hydroperoxides><Flavodoxin><Future><Genetic><Glutathione><Goals><H2O2><Hemi-Myeloperoxidase><Hospitals><Human><Hydrogen Peroxide><Hydroperoxide><Hydrophobicity><Hypochlorous Acid><Individual><Infection><KST gene><KST protein><Knowledge><Link><Lipid Hydroperoxide><Lipid Peroxidation><Lipid Peroxides><Lipids><Lipoperoxides><Marrow Neutrophil><Mediating><Medical><Membrane><Membrane Lipids><Modern Man><Morphogenesis><Myeloperoxidase><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nutrient><Organ><Oxidants><Oxidative Burst><Oxidizing Agents><PI4><Pathogenesis><Pathogenicity><Pathogenicity Factors><Pathway interactions><Permeability><Peroxidases><Peroxides><Phagosomes><Phosphatidylserines><Plasma Membrane><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Polyunsaturated Fatty Acids><Predisposition><Process><Protease Inhibitor 4><Proteins><Reaction><Resistance><Respiratory Burst><Role><S cerevisiae><S. cerevisiae><SERPINA4><SERPINA4 gene><Saccharomyces cerevisiae><Sepsis><Serine Phosphoglycerides><Stress><Susceptibility><Systemic infection><TRX gene><TRX protein><TRX1><TXN gene><Testing><Therapeutic><Therapeutic Fungicides><Thioredoxin><Tissue Kallikrein Inhibitor><Virulence><Virulence Factors><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging population><anti-fungal><anti-fungal agents><anti-fungal drug><anti-microbial peptide><blood infection><bloodstream infection><catalase><cell biology><cell damage><cell injury><cellular damage><damage to cells><design><designing><developmental><drug resistant><electron acceptor><extracellular><fungal pathogen><fungi pathogen><fungus><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><improved><injury to cells><kallistatin><leukocyte oxidative burst><lipid peroxide><membrane structure><morphogenetic process><neutrophil><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><oxidation><pathogenic fungus><pathway><plasmalemma><population aging><protection pathway><protective pathway><resistance strain><resistance to Drug><resistant><resistant strain><resistant to Drug><social role><synergism><therapeutic outcome><therapy outcome><uptake>