IL-33/ST2 INDEPENDENT ACTIVATION OF TYPE 2 RESPONSES IN ALLERGIC ASTHMA - PROJECT SUMMARY/ ABSTRACT THE IL-1 FAMILY CYTOKINE IL-33 PLAYS A ROLE IN MANY INFLAMMATORY DISEASES INCLUDING ATHEROSCLEROSIS, FIBROSIS, COPD, AND ASTHMA. AS A PLEOTROPIC ALARMIN, IL-33 IS AN INNATE MEDIATOR OF TH2 IMMUNITY AND A COVETED CLINICAL TARGET. HOWEVER, WHILE A-IL-33 THERAPEUTICS HAVE ADVANCED TO CLINICAL TRIALS, NONE HAVE BEEN EFFICACIOUS ENOUGH FOR REGULATORY APPROVAL. IN THE LITERATURE, MICE LACKING IL-33 (IL-33-/-) OR ST2 (ST2-/-) EXHIBIT REDUCED RESPONSES TO ALLERGENS, DEMONSTRATING THE NECESSITY OF IL-33/ST2 SIGNALING. PARADOXICALLY, IL-33-/- AND ST2-/- MICE IN OUR STUDIES RESPOND TO ALLERGEN COMPARABLY TO CONTROLS, INDICATING THAT ALTERNATIVE PATHWAYS TO INFLAMMATION CAN BE SUFFICIENT INDEPENDENT OF IL-33/ST2 SIGNALING. TO TEST WHETHER THESE IL-33/ST2-INDEPENDENT PATHWAYS ARE RELIANT ON ENVIRONMENTAL FACTORS, A HOUSE DUST MITE (HDM) MODEL OF ACUTE ALLERGIC INFLAMMATION WAS USED TO COMPARE THE ALLERGIC RESPONSES OF ST2-/- MICE FROM OUR FACILITY (FACILITY A) AND ANOTHER FACILITY (FACILITY B). CONSISTENT WITH AN ENVIRONMENTAL EFFECT, WE FOUND THAT ST2-/- MICE FROM FACILITY A EXHIBIT AN INCREASED INFLAMMATORY RESPONSE COMPARED TO THOSE FROM FACILITY B. HYPOTHESIZING THAT THE ENVIRONMENTAL INFLUENCE MAY BE DERIVED FROM THE MICROBIOME, WE PERFORMED 16S SEQUENCING ON FECAL SAMPLES FROM WT AND ST2-/- MICE IN EACH FACILITY. FACILITY A MICE HAD LOWER A-DIVERSITY THAN FACILITY B REGARDLESS OF GENOTYPE, INDICATIVE OF POTENTIAL DYSBIOSIS, AND B- DIVERSITY ANALYSIS SHOWED THAT BOTH FACILITY AND GENOTYPE CONTRIBUTE TO MICROBIOME VARIANCE. EXCITINGLY, WHILE ANTIBIOTIC DEPLETION DID NOT AFFECT THE MICE IN FACILITY B, THERE WAS A SIGNIFICANT DECREASE IN THE HDM RESPONSES OF ST2-/- MICE FROM FACILITY A. TOGETHER, THESE DATA DEMONSTRATE THAT IL-33/ST2-INDEPENDENT ALLERGIC PATHWAYS ARE UPREGULATED IN A MICROBIOME-DEPENDENT MANNER. BY DISCERNING THE ROLE OF THE MICROBIOME IN DRIVING ALTERNATIVE PATHWAYS TO ALLERGIC ACTIVATION, THE RELATIONSHIP BETWEEN THE ENVIRONMENT AND INNATE SIGNALING CAN BE BETTER UNDERSTOOD IN BROADER DISEASE CONTEXTS.