Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier
Lael M. Yonker, … , David R. Walt, Alessio Fasano
Lael M. Yonker, … , David R. Walt, Alessio Fasano
Published May 25, 2021
Citation Information: J Clin Invest. 2021;131(14):e149633. https://doi.org/10.1172/JCI149633.
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Clinical Research and Public Health Inflammation

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

Abstract

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 (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.METHODS Here, 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.RESULTS We 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.CONCLUSION These 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.

Authors

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

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Figure 3

Peak values of (A) anti–spike IgM, (B) anti–spike IgG, and (C) anti–spike IgA were quantified in plasma from children with MIS-C (n = 16), children with acute COVID-19 (n = 22), and pre-pandemic healthy controls (n = 32).

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Peak values of (A) anti–spike IgM, (B) anti–spike IgG, and (C) anti–spik...
Results were compared by 1-way ANOVA with multiple comparisons. Time course of (D) anti–spike IgM, (E) anti–spike IgG, and (F) anti–spike IgA were plotted over time following symptom onset for MIS-C. (G) The IC50 for antibody neutralization for children with MIS-C and children with acute COVID-19 were compared by Mann-Whitney t test. Mean values and the SD are presented. *P < 0.05, **P < 0.01, and ****P < 0.0001.