Project Grant K08AI177743

TARGETABLE PATHWAYS DRIVING SUB-OPTIMAL EARLY-LIFE CD8 T CELL RESPONSES - PROJECT SUMMARY SEVERE INFECTION IS ONE OF THE TOP THREE CAUSES OF NEONATAL MORTALITY, ACCORDING TO THE WORLD HEALTH ORGANIZATION. OF INFECTION-RELATED DEATHS, VIRUSES CAUSE 6.5% IN NEONATES AND 19.4% IN INFANTS. IN CHILDREN UNDER FIVE YEARS OF AGE, INFECTIONS WITH RESPIRATORY SYNCYTIAL VIRUS ACCOUNT FOR PARTICULARLY HIGH MORBIDITY AND MORTALITY RATES. THERE IS AN UNMET NEED TO UNDERSTAND BETTER AND MODULATE THE UNIQUE BIOLOGY OF EARLY CHILDHOOD IMMUNE CELLS, INCLUDING CYTOTOXIC CD8 T CELLS THAT ACT AS A DOUBLE-EDGED SWORD BY PROTECTING FROM INTRACELLULAR PATHOGENS INCLUDING VIRUSES WHILE ALSO CONTRIBUTING TO IMMUNOPATHOLOGY DURING SEVERE VIRAL BRONCHIOLITIS. THE FUNCTIONAL PROPERTIES AND THE MOLECULAR BASIS FOR THE UNIQUE FEATURES AND REMODELING OF CD8 T CELLS IN EARLY CHILDHOOD REMAIN LARGELY UNDEFINED IN HUMANS, LIMITING THE ADVANCEMENT OF THERAPEUTIC MODULATORS. NEONATES HAVE LOWER CD8 T COUNTS THAN ADULTS, AND THEIR CD8 T CELLS HAVE A SHORTER LIFE SPAN. MOREOVER, STUDIES IN THE FIELD HAVE FOUND THAT NEONATAL CD8 T CELLS UNDERGO RAPID PROLIFERATION AND TERMINAL DIFFERENTIATION AS EFFECTOR CELLS AT THE EXPENSE OF FORMING LONG-LIVED MEMORY CELLS. BOTH NEONATES AND PATIENTS WITH AN IMMUNE DEFICIENCY CALLED ACTIVATED PI3K-DELTA SYNDROME (APDS) SUFFER FROM SEVERE VIRAL INFECTIONS AND HAVE SIMILARLY ATYPICAL CD8 T CELL FUNCTION. WE HYPOTHESIZE THAT EARLY-LIFE CD8 T CELLS HAVE A DECREASED THRESHOLD FOR PI3K/MTOR ACTIVATION, WHICH ENHANCES EFFECTOR ACTIVITY AND AUGMENTS SHORT-LIVED EFFECTOR CYTOTOXIC T CELL FATES THAT CAN CONTRIBUTE TO IMMUNOPATHOLOGY IN SEVERE VIRAL BRONCHIOLITIS. BY COMPARING HUMAN NEONATAL, CHILD, YOUNG ADULT, AND MODERATE VS. SEVERE RSV BRONCHIOLITIS PATIENT CD8 T CELLS IN VITRO, AIM 1 WILL DEFINE MECHANISMS DRIVING INCREASED PROLIFERATION, GLYCOLYSIS, AND CELL DEATH IN EARLY-LIFE CD8 T CELLS AND AIM 2 WILL DETERMINE ROLES OF PI3K/MTOR PATHWAYS IN T CELL FUNCTION DURING RSV BRONCHIOLITIS AND THEIR RELATIONSHIP WITH DISEASE SEVERITY. THIS RESEARCH WILL LEAD TO FURTHER INSIGHTS INTO HOW EARLY-LIFE CD8 T CELLS DIFFER FUNCTIONALLY FROM THOSE OF ADULTS AND WHAT PATHWAYS COULD SERVE AS TARGETS FOR INTERVENTIONS TO IMPROVE IMMUNE RESPONSES AND OUTCOMES OF SEVERE EARLY-LIFE INFECTION. NINA BRODSKY, M.D., IS AN ASSISTANT PROFESSOR IN PEDIATRIC CRITICAL CARE AT YALE UNIVERSITY SCHOOL OF MEDICINE. HER CAREER GOAL IS TO BECOME AN INDEPENDENT PRINCIPAL INVESTIGATOR LEADING TRANSLATIONAL RESEARCH EFFORTS AND TO BECOME PROFICIENT IN DEVELOPING TARGETED TRANSLATIONAL THERAPIES TO IMPROVE OUTCOMES FOR PATIENTS WHO SUFFER FROM SEVERE INFECTION AND IMMUNE-MEDIATED DISEASES. THIS CAREER DEVELOPMENT AWARD WILL ALLOW DR. BRODSKY TO 1) HONE HER SKILLS IN IMMUNOLOGIC, OMICS, AND TRANSLATIONAL RESEARCH METHODS UNDER THE DIRECTION OF A MENTORING TEAM THAT IS AT THE FOREFRONT OF RESEARCH IN T CELL FUNCTION, SIGNALING AND METABOLISM AND 2) IDENTIFY PROMISING MOLECULAR TARGETS FOR INTERVENTION TO IMPROVE OUTCOMES OF SEVERE INFECTION FOR HER FUTURE RESEARCH.