Journal Article

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

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

2021

Overview

BACKGROUNDWeeks after SARS-CoV-2 infection or exposure, some children develop a severe, life-threatening illness called multisystem inflammatory syndrome in children (MIS-C). Gastrointestinal (GI) symptoms are common in patients with MIS-C, and a severe hyperinflammatory response ensues with potential for cardiac complications. The cause of MIS-C has not been identified to date.METHODSHere, we analyzed biospecimens from 100 children: 19 with MIS-C, 26 with acute COVID-19, and 55 controls. Stools were assessed for SARS-CoV-2 by reverse transcription PCR (RT-PCR), and plasma was examined 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 a proof of concept, we treated a patient with MIS-C with larazotide, a zonulin antagonist, and monitored the effect on antigenemia and the patient's clinical response.RESULTSWe showed that in children with MIS-C, a prolonged presence of SARS-CoV-2 in the GI tract led to the release of zonulin, a biomarker of intestinal permeability, with subsequent trafficking of SARS-CoV-2 antigens into the bloodstream, leading to hyperinflammation. The patient with MIS-C treated with larazotide had a coinciding decrease in plasma SARS-CoV-2 spike antigen levels and inflammatory markers and a resultant clinical improvement above that achieved with currently available treatments.CONCLUSIONThese mechanistic data on 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.

• Publisher: American Society for Clinical Investigation
• Subject: Adolescent / Antigenemia / Antigens / Antigens, Viral - blood / Biomarkers / Biomarkers - blood / Biomedical research / Case-Control Studies / Child / Child, Preschool / Children / Coronaviruses / COVID-19 / COVID-19 - etiology / COVID-19 - physiopathology / COVID-19 - virology / Cytokine storm / Disease prevention / Female / Gastrointestinal mucosa / Gastrointestinal tract / Haptoglobins - antagonists & inhibitors / Haptoglobins - physiology / Health aspects / Humans / Illnesses / Immune response / Infant / Infant, Newborn / Infections / Inflammation / Intestinal Mucosa - drug effects / Intestinal Mucosa - physiopathology / Intestinal Mucosa - virology / Kawasaki disease / Male / Membrane proteins / Mucosa / Multisystem inflammatory syndrome in children / Oligopeptides - pharmacology / Pathogenesis / Patients / Pediatric research / Permeability / Permeability - drug effects / Physiological aspects / Plasma / Polymerase chain reaction / Proof of Concept Study / Protein Precursors - antagonists & inhibitors / Protein Precursors - blood / Protein Precursors - physiology / Proteins / Reverse transcription / SARS-CoV-2 - immunology / SARS-CoV-2 - pathogenicity / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - blood / Spike Glycoprotein, Coronavirus - immunology / Systemic Inflammatory Response Syndrome - etiology / Systemic Inflammatory Response Syndrome - physiopathology / Systemic Inflammatory Response Syndrome - virology / T cell receptors / Young Adult