Project Grant F31AI203277

ENVIRONMENTALLY SHAPED MULTI-OMIC RESPONSES TO RHINOVIRUS INFECTION IN AMISH AND HUTTERITE CHILDREN - PROJECT SUMMARY/ABSTRACT ASTHMA IS ONE OF THE MOST COMMON CHRONIC DISEASES OF CHILDHOOD. EARLY-LIFE RHINOVIRUS (RV) WHEEZING ILLNESSES ARE THE STRONGEST PREDICTORS OF DEVELOPING ASTHMA IN CHILDHOOD, AND VIRAL INFECTIONS ARE THE MOST COMMON TRIGGERS OF ASTHMA EXACERBATIONS. YET THE MOLECULAR MECHANISMS THAT SHAPE INDIVIDUAL VARIATION IN ANTIVIRAL IMMUNE RESPONSES, PARTICULARLY THE INFLUENCE OF EARLY-LIFE ENVIRONMENTAL EXPOSURES, REMAIN POORLY UNDERSTOOD. CHILDREN EXPOSED TO ANIMAL BARNS EARLY IN LIFE, SUCH AS THE AMISH, HAVE REMARKABLY LOWER RATES OF ASTHMA AND WHEEZING ILLNESSES COMPARED TO THOSE RAISED IN INDUSTRIALIZED FARMING SETTINGS, SUCH AS THE HUTTERITES. BECAUSE THESE POPULATIONS SHARE SIMILAR GENETIC ANCESTRY BUT DIFFER PROFOUNDLY WITH RESPECT TO EARLY-LIFE MICROBIAL EXPOSURES, THEY PROVIDE A POWERFUL NATURAL MODEL TO DISENTANGLE ENVIRONMENTAL FROM GENETIC INFLUENCES ON IMMUNE REGULATION. THIS FELLOWSHIP PROPOSES A MULTI-OMIC INVESTIGATION OF THE TRANSCRIPTIONAL AND EPIGENETIC RESPONSES TO RV INFECTION IN TWO IMMUNE CELL TYPES WHOSE ABUNDANCES DIFFER SIGNIFICANTLY BETWEEN AMISH AND HUTTERITE CHILDREN: CD8+CD28NULL T CELLS AND CD19+ B CELLS. USING IN VITRO RV STIMULATION OF PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM AMISH AND HUTTERITE CHILDREN, WE WILL SORT THESE CELLS AND GENERATE HIGH QUALITY, DEEP RNA-SEQUENCING AND DNA METHYLATION PROFILES TO CHARACTERIZE POPULATION-SPECIFIC REGULATORY RESPONSES TO RV STIMULATION. AIM 1 WILL IDENTIFY RV-INDUCED AND POPULATION-SPECIFIC DIFFERENTIALLY EXPRESSED AND DIFFERENTIALLY SPLICED GENES, FOLLOWED BY PATHWAY-ENRICHMENT ANALYSES TO IDENTIFY DIFFERENTIALLY RESPONSIVE BIOLOGICAL PROCESSES. AIM 2 WILL CHARACTERIZE RV-INDUCED AND POPULATION-SPECIFIC DNA METHYLATION CHANGES IN THE SAME SORTED IMMUNE CELLS USED IN AIM 1. AIM 3 WILL INTEGRATE TRANSCRIPTIONAL AND METHYLATION DATA TO IDENTIFY METHYLATION-EXPRESSION ASSOCIATIONS (EXPRESSION QUANTITATIVE TRAIT METHYLATION, EQTM) THAT DIFFER BY POPULATION AND TREATMENT. PATHWAY ENRICHMENT ANALYSES BASED ON EQTM RESULTS WILL IDENTIFY TRANSCRIPTIONAL PROGRAMS THAT MAY BE INFLUENCED BY EPIGENETIC REGULATION AND CONTRIBUTE TO DIVERGENT ANTIVIRAL RESPONSES. TOGETHER, THESE STUDIES WILL PROVIDE ONE OF THE MOST COMPREHENSIVE CHARACTERIZATIONS OF HOW EARLY-LIFE ENVIRONMENTS SHAPE ANTIVIRAL RESPONSES AT THE MOLECULAR LEVEL. THIS WORK WILL PROVIDE A FOUNDATION FOR FUTURE STUDIES INVESTIGATING HOW THESE MECHANISMS MAY CONTRIBUTE TO ASTHMA SUSCEPTIBILITY AND ASTHMA EXACERBATION SEVERITY.