Project Grant R01AI177615

FUNGAL-BACTERIAL DYNAMICS DRIVING DYSREGULATED HOST RESPONSES AND LETHAL SYNERGISM - POLYMICROBIAL INFECTIONS INVOLVING FUNGAL AND BACTERIAL PATHOGENS ARE INCREASINGLY COMMON AMONG HOSPITALIZED PATIENTS. HOWEVER, THERE IS A PAUCITY OF RESEARCH FOCUSED ON STUDYING POLYMICROBIAL INFECTIONS. THE FUNGAL PATHOGEN CANDIDA ALBICANS IS THE MOST COMMON CAUSE OF INVASIVE FUNGAL INFECTION AND THE THIRD MOST COMMON CAUSE OF NOSOCOMIAL BLOODSTREAM INFECTIONS IN THE US. INVASIVE FUNGAL INFECTIONS WITH C. ALBICANS HAVE DEVASTATINGLY HIGH MORTALITY RATES COMPARED WITH BACTERIAL INFECTIONS. BLOODSTREAM FUNGAL INFECTIONS, WHICH ARE MOSTLY MONOMICROBIAL, RESULT IN A 40% MORTALITY RATE. IN CONTRAST, INTRA-ABDOMINAL FUNGAL INFECTIONS (IAI), WHICH ARE OFTEN POLYMICROBIAL INVOLVING BOTH FUNGAL AND BACTERIAL SPECIES, RESULT IN A 50-75% MORTALITY RATE, WHICH FAR EXCEEDS BACTERIAL MONO- OR POLYMICROBIAL IAI MORTALITY RATES (20%). FUNGAL INVOLVEMENT ALSO LEADS TO INCREASED RATES OF RELAPSE AND MORE SEVERE DISEASE SCORES. THE MECHANISMS ASSOCIATED WITH THIS EXACERBATED MORTALITY ARE CURRENTLY UNKNOWN. THE OBJECTIVE OF THIS PROPOSAL IS TO DELINEATE HOST AND MICROBIAL MECHANISMS CONTRIBUTING TO SYNERGISTIC LETHALITY DURING POLYMICROBIAL FUNGAL-BACTERIAL IAI. OUR CENTRAL HYPOTHESIS IS THAT POLYMICROBIAL FUNGAL-BACTERIAL IAIS PROMOTE SYNERGISTIC EFFECTS ON MORTALITY INDUCED BY MICROBE-MICROBE INTERACTIONS THAT INCREASE BACTERIAL TOXIN PRODUCTION, LEADING TO UPREGULATION OF IMMUNE SIGNALING PATHWAYS, DYSREGULATION OF HEMOSTASIS AND COAGULATION, AND ALTERED BONE MARROW REMODELING. THIS HYPOTHESIS WILL BE TESTED BY MODELING POLYMICROBIAL INTERACTIONS WITH C. ALBICANS AND THE GRAM-POSITIVE BACTERIUM STAPHYLOCOCCUS AUREUS, WHICH IS THE MOST COMMONLY CO-ISOLATED BACTERIAL PATHOGEN FROM FUNGAL-BACTERIAL CO-INFECTIONS. THE FIRST SPECIFIC AIM OF THIS PROJECT IS TO INTERROGATE THE MECHANISMS BY WHICH CANDIDA INDUCES OF S. AUREUS TOXIN PRODUCTION DURING POLYMICROBIAL IAI. THE SECOND SPECIFIC AIM WILL DEFINE BACTERIAL MECHANISMS AND VIRULENCE REGULATORS THAT DRIVE DYSREGULATED HEMOSTASIS AND COAGULATION THAT CONTRIBUTE TO LETHALITY DURING POLYMICROBIAL IAI. THE THIRD SPECIFIC AIM WILL FUNCTIONALLY CHARACTERIZE THE CONSEQUENCES OF CANDIDA-INDUCED S. AUREUS TOXIN PRODUCTION ON BONE MARROW HOMEOSTASIS AND TRAINED INNATE IMMUNITY. COMPLETION OF THIS PROJECT WILL IDENTIFY BOTH NEW MECHANISMS THAT UNDERLIE EXACERBATED PATHOGENICITY OF POLYMICROBIAL INFECTIONS AND THERAPEUTIC APPROACHES TO IMPROVE OUTCOMES OF IAI.