Proteomic Profiling of MIS-C Patients Reveals Heterogeneity Relating to Interferon Gamma Dysregulation and Vascular Endothelial Dysfunction

Diorio, C.; Shraim, R.; Vella, L. A.; Giles, J. R.; Baxter, A. E.; Oldridge, D. A.; Canna, S. W.; Henrickson, S. E.; McNerney, K. O.; Balamuth, F.; Burudpakdee, C.; Lee, J.; Leng, T.; Farrel, A.; Lambert, M. P.; Sullivan, K. E.; Wherry, E. J.; Teachey, D. T.; Bassiri, H.; Behrens, E. M.

Multi-system Inflammatory Syndrome in Children (MIS-C) is a major complication of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic in pediatric patients. Weeks after an often mild or asymptomatic initial infection with SARS-CoV-2 children may present with a severe shock-like picture and marked inflammation. Children with MIS-C present with varying degrees of cardiovascular and hyperinflammatory symptoms. We performed a comprehensive analysis of the plasma proteome of more than 1400 proteins in children with SARS-CoV-2. We hypothesized that the proteome would reflect heterogeneity in hyperinflammation and vascular injury, and further identify pathogenic mediators of disease. Protein signatures demonstrated overlap between MIS-C, and the inflammatory syndromes macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). We demonstrate that PLA2G2A is a key marker of MIS-C that associates with TMA. We found that IFN{gamma} responses are dysregulated in MIS-C patients, and that IFN{gamma} levels delineate clinical heterogeneity.