1. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier
- Author
-
Yonker, Lael M., Gilboa, Tal, Ogata, Alana F., Senussi, Yasmeen, Lazarovits, Roey, Boribong, Brittany P., Bartsch, Yannic C., Loiselle, Maggie, Rivas, Magali Noval, Porrit, Rebecca A., Lima, Rosiane, Davis, Jameson P., Farkas, Eva J., Burns, Madeleine D., Young, Nicola, Mahajan, Vinay S., Hajizadeh, Soroush, Lopez, Xcanda I. Herrera, Kreuzer, Johannes, Morris, Robert, Martinez, Enid E., Han, Isaac, Griswold, Kettner, Jr., Barry, Nicholas C., Thompson, David B., Church, George, Edlow, Andrea G., Haas, Wilhelm, Pillai, Shiv, Arditi, Moshe, Alter, Galit, Walt, David R., and Fasano, Alessio
- Subjects
Gastrointestinal mucosa -- Health aspects -- Physiological aspects ,Membrane proteins -- Health aspects -- Physiological aspects ,Pediatric research ,Health care industry - 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 SARSCoV-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., Introduction Most children who are acutely infected with SARS-CoV-2 develop mild upper respiratory symptoms or experience asymptomatic infection. Several days to weeks after resolution of the initial infection, some of [...]
- Published
- 2021
- Full Text
- View/download PDF