Project Grant R01HL173059

DEFINING NEUTROPHIL PATHOBIOLOGY IN PEDIATRIC LONG COVID - OVER 15.6 MILLION CHILDREN IN THE U.S. ALONE HAVE BEEN INFECTED BY SARS-COV2. WHILE MOST RECOVER, ROUGHLY 1 MILLION CHILDREN SUFFER FROM LONG COVID. NEUTROPHILS HAVE BEEN SHOWN TO BE HYPERACTIVATED IN LONG COVID, WHICH IS CONCERNING BECAUSE THEY CAN BE QUITE INFLAMMATORY, CAUSING VASCULAR AND TISSUE DAMAGE AND CONTRIBUTING TO DISEASE. WE AIM IS TO DEFINE THE NEUTROPHIL PROFILES DRIVING LONG COVID IN ORDER TO ULTIMATELY OFFER NOVEL STRATEGIES FOR DIAGNOSING AND TREATING THIS NEW DISEASE. TO ACHIEVE THIS GOAL, WE WILL USE BOTH SINGLE-CELL RNA SEQUENCING TECHNOLOGY TO DEFINE NEUTROPHIL ACTIVATION PROFILES AND MICROFLUIDICS TO TEST NEUTROPHIL FUNCTIONALITY LONG COVID, COMPARED TO HEALTHY CONTROLS. OUR CENTRAL HYPOTHESIS IS THAT NEUTROPHIL ACTIVATION IN LONG COVID CARRIES A DISTINCT NEUTROPHILIC GENE EXPRESSION AND FUNCTIONAL PROFILE, WHICH CONTRIBUTES TO PATHOGENICITY. IMPORTANTLY, WE AIM TO PARTNER WITH AN EXISTING CLINICAL TRIAL OF LARAZOTIDE FOR LONG COVID (CLINICALTRIALS.GOV IDENTIFIER: NCT05747534) TO TEST REVERSIBILITY OF NEUTROPHIL ACTIVATION BY TARGETING SOURCES OF SPIKE ANTIGENEMIA. ULTIMATELY, MECHANISMS DRIVING THE PATHOGENESIS OF THIS NEWLY EMERGED POST-COVID-19- RELATED ILLNESS MUST BE DEFINED TO ESTABLISH DIAGNOSTICS AND EFFECTIVE THERAPIES.