Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier.

Yonker, Lael M; Gilboa, Tal; Ogata, Alana F; Senussi, Yasmeen; Lazarovits, Roey; Boribong, Brittany P; Bartsch, Yannic C; Loiselle, Maggie; Noval Rivas, Magali; Porritt, Rebecca A; Lima, Rosiane; Davis, Jameson P; Farkas, Eva J; Burns, Madeleine D; Young, Nicola; Mahajan, Vinay S; Hajizadeh, Soroush; Herrera Lopez, Xcanda I; Kreuzer, Johannes; Morris, Robert; Martinez, Enid E; Han, Isaac; Griswold, Kettner; Barry, Nicholas C; Thompson, David B; Church, George; Edlow, Andrea G; Haas, Wilhelm; Pillai, Shiv; Arditi, Moshe; Alter, Galit; Walt, David R; Fasano, Alessio

BACKGROUND Weeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called Multisystem Inflammatory Syndrome in Children (MIS-C). Gastrointestinal symptoms are common in MIS-C patients and severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not previously been identified. METHODS Here, we analyzed biospecimens from 100 children: 19 children with MIS-C, 26 with acute COVID-19, and 55 controls. Stool was assessed for SARS-CoV-2 by RT-PCR and plasma was assessed for markers of breakdown of mucosal barrier integrity, including zonulin. Ultrasensitive antigen detection was used to probe for SARS-CoV-2 antigenemia in plasma, and immune responses were characterized. As proof of concept, we treated a MIS-C patient with larazotide, a zonulin antagonist, and monitored impact on antigenemia and clinical response. RESULTS We showed that in MIS-C, prolonged presence of SARS-CoV-2 in the GI tract leads to release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The MIS-C patient treated with larazotide displayed a coinciding decrease in plasma SARS-CoV-2 Spike antigen levels, inflammatory markers, and a resultant clinical improvement above that achieved with currently available treatments. CONCLUSION These mechanistic data of MIS-C pathogenesis provide insight into targets for diagnosing, treating, and preventing MIS-C, which are urgently needed for this increasingly common severe COVID-19-related disease in children.