Project Grant F32AI202787

ECOLOGICAL AND MOLECULAR MECHANISMS LINKING B-LACTAM EXPOSURE TO ENTEROCOCCUS FAECIUM STRAIN DYNAMICS AND BLOODSTREAM INFECTION RISK - PROJECT SUMMARY ENTEROCOCCUS FAECIUM BLOODSTREAM INFECTIONS ARE AN EMERGING CAUSE OF MORBIDITY AND MORTALITY IN IMMUNOCOMPROMISED PATIENTS. THESE INFECTIONS TYPICALLY ARISE FROM GUT-TO-BLOOD TRANSLOCATION AND ARE ALMOST ALWAYS PRECEDED BY E. FAECIUM INTESTINAL DOMINATION AFTER ANTIBIOTIC-DRIVEN DYSBIOSIS. YET, MOST PATIENTS WITH INTESTINAL DOMINATION NEVER DEVELOP INVASIVE DISEASE. UNDERSTANDING WHY ONLY SOME PATIENTS PROGRESS TO BLOODSTREAM INFECTION AND HOW ANTIBIOTIC EXPOSURE MODIFIES THAT RISK CAN ELUCIDATE THE ECOLOGICAL AND MOLECULAR MECHANISMS GOVERNING PROGRESSION FROM INTESTINAL DOMINATION TO INFECTION. THE LONG-TERM OBJECTIVE OF THIS FELLOWSHIP IS TO UNCOVER THESE MECHANISMS, WHICH WILL PAVE THE WAY FOR INFORMING ANTIBIOTIC STEWARDSHIP AND PREVENTIVE STRATEGIES FOR HIGH-RISK PATIENTS. THE CANDIDATE'S PRELIMINARY ANALYSES OF CLINICAL LONGITUDINAL MICROBIOME DATA SHOW THAT PATIENTS TEND TO HARBOR MULTIPLE E. FAECIUM STRAINS, AND THAT ABRUPT STRAIN TURNOVER FREQUENTLY FOLLOWS B-LACTAM EXPOSURE. COHORT-WIDE MODELING IN >1,000 TRANSPLANT PATIENTS FURTHER REVEALS THAT B-LACTAMS ARE STRONGLY ASSOCIATED WITH INCREASED INFECTION RISK. BUILDING ON THIS SOLID PRELIMINARY FOUNDATION, WE WILL INVESTIGATE HOW B-LACTAM TREATMENT IMPACTS E. FAECIUM POPULATION DYNAMICS WITHIN PATIENTS' MICROBIOMES, RESHAPING INFECTION RISK, AND IDENTIFY THE MOLECULAR MECHANISMS THAT ENABLE SPECIFIC STRAINS TO GAIN A COMPETITIVE ADVANTAGE UNDER B-LACTAM PRESSURE. AIM 1 INTEGRATES LONG-READ METAGENOMICS OF BIOBANKED STOOL SAMPLES WITH A MOUSE MODEL THAT REPRODUCES ANTIBIOTIC-DRIVEN DOMINATION, NEUTROPENIA, AND B-LACTAM THERAPY TO TEST WHETHER B-LACTAMS SELECTIVELY ENRICH STRAINS WITH HIGHER DISSEMINATION POTENTIAL. AIM 2 WILL IDENTIFY THE MOLECULAR BASIS OF B-LACTAM-ASSOCIATED STRAIN TURNOVER BY INTEGRATING ANTIBIOTIC SUSCEPTIBILITY ASSAYS, STRAIN-COMPETITION EXPERIMENTS, WHOLE-GENOME SEQUENCING, TRANSCRIPTOMICS, AND GENETIC ENGINEERING. WE WILL FOCUS ON HOW STRUCTURAL VARIANTS NEAR PBP5, A MAIN LOCUS OF B-LACTAM RESISTANCE, MODULATE GENE EXPRESSION AND B-LACTAM TOLERANCE. TOGETHER, THESE STUDIES WILL REVEAL HOW ECOLOGICAL PROCESSES AND GENOMIC VARIATION INTERSECT TO DETERMINE INFECTION RISK. THIS FELLOWSHIP OFFERS COMPREHENSIVE TRAINING IN MICROBIAL ECOLOGY, PATHOGEN EVOLUTION, AND TRANSLATIONAL INFECTIOUS DISEASE. THE APPLICANT WILL AUGMENT EXPERTISE IN COMPUTATIONAL GENOMICS WITH TRAINING IN LONG-READ METAGENOMICS, STRUCTURAL VARIANT DISCOVERY, MICROBIAL POPULATION GENETICS, LONGITUDINAL CLINICAL MODELING, AND MECHANISTIC EXPERIMENTAL DESIGN. RESEARCH WILL TAKE PLACE WITHIN THE HIGHLY COLLABORATIVE XAVIER LAB AT MEMORIAL SLOAN KETTERING CANCER CENTER, WITH ACCESS TO LARGE-SCALE CLINICAL MICROBIOME DATASETS, BIOBANKED SAMPLES, ADVANCED SEQUENCING PLATFORMS, AND EXPERT COLLABORATORS. THROUGH STRUCTURED MENTORSHIP, COURSEWORK, AND INTEGRATED COMPUTATIONAL AND EXPERIMENTAL WORK, THE FELLOWSHIP WILL PREPARE THE APPLICANT FOR AN INDEPENDENT RESEARCH CAREER IN MICROBIOME AND INFECTIOUS DISEASE RESEARCH.