Abstract 11966: Translational Cardioinformatics: Neutrophil-Derived Translocator Protein as a Novel Regulator of Myocarditis and Coronary Artery Aneurysm in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Abstract

Introduction: Cardiovascular disease (CVD) in Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) lead to increased mortality through myocardial infarction. Hypothesis: Since KD and MIS-C are shaped by the same immune continuum, the cardiac pathologies and lethal complications may be averted by targeting a key regulator controlling both diseases; however, the pathogenic drivers are largely undefined. Methods: Through integrated, multi-cohort, single-cell meta-analysis of KD and MIS-C PBMC scRNA-seq profiles, we investigated the immunological drivers associated with systemic damage and cardiac pathologies, compared with other pediatric diseases, and validated across independent cohorts of KD, MIS-C, and myocardial infarction. Via cheminformatics approaches, we identified FDA-approved drugs for repurposing. Results: We found the expansion and hyperactivation of CD177 + neutrophils in KD and MIS-C, but not in other pediatric diseases. CD177 + neutrophils overexpressed markers and causal mediators of CVD development, supported by activation of prognostic CVD gene signatures (acute CVD, major adverse cardiovascular and limb events, and myocardial infarction). CD177 + neutrophils’ overactivated effector repertoire may mediate systemic inflammation and molecular damage via a vascular homing mechanism. We identified a dysfunctional SPI1-dependent regulatory network shared by KD and MIS-C during neutrophil hyperactivation, as well as key regulators which may induce cardiac disorders. Importantly, we found that TSPO is associated with myocarditis and coronary artery aneurysm, disease severity, IVIG treatment, and patient recovery. Via independent cohorts analyses, we validated TSPO as a prime target against KD and MIS-C pathologies. Murine myocardial infarction model confirmed the cardiac hyper-infiltration of hyperactivated CD177 + neutrophils. Lastly, we identified FDA-approved drugs against KD and MIS-C neutrophil hyperactivation. Conclusions: Collectively, CD177 + neutrophils have a pivotal role in KD/MIS-C systemic pathologies, clinical severity, and prognosis. We suggest drugs that can be developed as a single therapeutic strategy against either KD or MIS-C for clinical translation.