Project Grant K08AI182486

ALTERED CD4+ T CELL RESPONSES AND RESULTANT ASTHMA FOLLOWING NEONATAL HUMAN METAPNEUMOVIRUS INFECTION - HUMAN METAPNEUMOVIRUS (HMPV) IS A LEADING CAUSE OF LOWER RESPIRATORY TRACT INFECTION IN CHILDHOOD AND IS ASSOCIATED WITH INCREASED MORBIDITY AND MORTALITY IN NEONATES AND YOUNG INFANTS. ADDITIONALLY, YOUNG CHILDREN DIAGNOSED WITH HMPV BRONCHIOLITIS ARE AT INCREASED RISK OF DEVELOPING ASTHMA, WHICH IS THE MOST COMMON CHRONIC CONDITION OF CHILDHOOD. ASTHMA IN CHILDHOOD IS LARGELY MEDIATED BY A SUBSET OF CD4+ T CELLS, KNOWN AS TH2 CELLS, WHICH CONTRIBUTE TO MUCUS PRODUCTION, EOSINOPHIL RECRUITMENT, AND AIRWAY HYPERRESPONSIVENESS. HOWEVER, THE MECHANISTIC CONNECTION BETWEEN EARLY LIFE VIRAL INFECTION AND THE SUBSEQUENT DEVELOPMENT OF TH2- DRIVEN ASTHMA IS UNKNOWN, THUS LIMITING THERAPEUTIC AND PREVENTATIVE STRATEGY DEVELOPMENT. ONE CONTRIBUTING FACTOR TO THE ACUTE AND LONG-TERM PATHOLOGY OF RESPIRATORY VIRAL INFECTION COULD BE UNDERLYING DIFFERENCES IN THE DEVELOPING NEONATAL IMMUNE SYSTEM. THE NEONATAL IMMUNE SYSTEM IS REGULATED DIFFERENTLY THAN ADULTS, AS NEONATES GENERALLY MOUNT ANTI-INFLAMMATORY AND TOLEROGENIC RESPONSES. PRIOR LITERATURE HAS ALSO DEMONSTRATED THAT NEONATAL CD4+ T CELL DIFFERENTIATION TENDS TO FAVOR DEVELOPMENT OF TH2 CELLS WHEN COMPARED TO ADULTS. WE DEVELOPED A NEW NEONATAL HMPV MOUSE MODEL TO EVALUATE NEONATAL CD4+ T CELL RESPONSES. NEONATAL MICE INFECTED WITH HMPV INTRANASALLY ON DAY OF LIFE 4-6 MOUNTED AN INCREASED TH2 RESPONSE COMPARED TO ADULTS, WHILE ADULT MICE EXHIBITED A ROBUST ANTIVIRAL TH1 CD4+ RESPONSE. MOREOVER, TH2 CELLS GENERATED FOLLOWING NEONATAL INFECTION PERSISTED AS TISSUE RESIDENT MEMORY (TRM) CELLS. IN A LATE RE-CHALLENGE MODEL, MICE INITIALLY EXPOSED TO HMPV AS NEONATES MOUNTED A STRONG TH2 RESPONSE TO RE-INFECTION IN ADULTHOOD CHARACTERIZED BY EOSINOPHIL RECRUITMENT, MUCUS PRODUCTION, AND AIRWAY HYPERRESPONSIVENESS CONSISTENT WITH ASTHMA. USING AN ADOPTIVE TRANSFER MODEL WITH NEONATAL RECIPIENTS, OUR PRELIMINARY STUDIES SUGGEST THAT TH1 DIFFERENTIATION IS EXTRINSICALLY SUPPRESSED BY A LYMPHOCYTE POPULATION IN THE NEONATE, WHICH WE HYPOTHESIZE TO BE REGULATORY T CELLS (TREGS). ADDITIONALLY, PRELIMINARY SINGLE CELL RNA SEQUENCING EXPERIMENTS SUGGEST THAT NEONATAL CD4+ T CELLS USE DIFFERENT METABOLIC PATHWAYS COMPARED TO ADULTS; CELL METABOLISM HAS BEEN CONNECTED TO T CELL DIFFERENTIATION. COLLECTIVELY, OUR PRELIMINARY DATA DEMONSTRATE THAT NEONATES MOUNT A TH2-DOMINANT RESPONSE, EXHIBIT INCREASED TREG ACTIVITY, AND DEMONSTRATE ALTERED T CELL METABOLISM COMPARED TO ADULTS. THE CENTRAL HYPOTHESIS OF THIS PROPOSAL IS THAT EXTRINSIC SUPPRESSION OF TH1 DIFFERENTIATION BY TREGS AND INTRINSIC METABOLIC PREFERENCES PROMOTING TH2 FORMATION LEAD TO PREFERENTIAL DIFFERENTIATION OF NEONATAL CD4+ T CELLS INTO TH2S THAT PERSIST AND CONTRIBUTE TO ASTHMA PATHOGENESIS. WE PROPOSE THREE SPECIFIC AIMS: 1) TO EVALUATE TISSUE RESIDENT MEMORY (TRM) CD4+ T CELL CONTRIBUTIONS TO ASTHMA PATHOLOGY FOLLOWING NEONATAL HMPV INFECTION; 2) TO DETERMINE THE ROLE OF REGULATORY T CELLS IN TH1 SUPPRESSION IN THE NEONATAL LUNG FOLLOWING PRIMARY HMPV INFECTION; AND 3) TO DEFINE THE ROLE OF ALTERED NEONATAL CD4+ T CELL METABOLISM ON DIFFERENTIATION/SKEWING. THIS PROPOSAL WILL MECHANISTICALLY EVALUATE THE ALTERED NEONATAL CD4+ T CELL RESPONSES TO HMPV AND THEIR ROLE IN ASTHMA DEVELOPMENT.