Comments for:

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.
View: Text | PDF
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

×

Treating persisting intestinal SARS-CoV-2 infection to prevent MIS-C – a role for GS-441524?

Submitter: Martin Alberer | martin.alberer@lrz.uni-muenchen.de

Authors: Martin Alberer, Katrin Hartmann, Kaspar Matiasek, Regina Hofmann-Lehmann, Sandra Felten, Marina L. Meli, and Ulrich von Both

Hauner Children’s Hospital, University Hospital, Ludwig-Maximilians-University, Munich, Germany

Published June 8, 2021

To the editor,

With great interest we have read the report of Yonker et al. on zonulin-dependent loss of gut mucosal barrier function in children with multisystem inflammatory syndrome (MIS-C) (1). The authors postulate the translocation of SARS-CoV-2 antigens into the bloodstream, due to intestinal leackage, to trigger the characteristic systemic inflammation seen in MIS-C. Along this line, persisting SARS-CoV-2-associated intestinal dysbiosis is proposed to upregulate zonulin levels and thereby to increase intestinal permeability. SARS-CoV-2-RNA was detected in consecutive stool samples in most patients with MIS-C, even a long time after initial SARS-CoV-2 infection. As proof of concept, the authors successfully treated a 17-month-old boy with MIS-C using the zonulin antagonist larazotide after the child had failed to improve on anti-inflammatory therapy. Larazotide treatment resulted in a decrease of SARS-CoV-2 antigenemia and of inflammatory markers mirrored by a substantial clinical improvement of the patient.

In addition to this intriguing finding, we propose that antiviral treatment of persisting intestinal SARS-CoV-2 infection might be a key intervention in treating pediatric patients with MIS-C. GS-441524 is the main metabolite of remdesivir, a prodrug of the nucleoside analogue which has been used with limited success in patients with acute COVID-19 (2). In contrast to remdesivir, GS-441524 can be taken up orally and has been shown to effectively treat other coronavirus-associated diseases, such as feline infectious peritonitis (FIP), a deadly disease in cats caused by systemic infection of the primary enteric feline coronavirus (FCoV) (2, 3). In addition, a similar adenosine analogue has been successfully used to eradicate persisting intestinal FCoV infection in cats (4). As we have previously proposed, there exists a striking clinical resemblance between FIP and MIS-C (5). In both clinical scenarios, persisting intestinal coronavirus infection triggers a systemic inflammatory vasculitis possibly caused by hyperactivation of monocytes and increased cytokine release in a subset of young human individuals and cats, respectively. Besides the possibility to eliminate a persisting SARS-CoV-2 infection in the intestine, it has been shown that GS-441524 is sufficiently absorbed via the oral route in dogs and mice and might also be a treatment option of systemic human coronavirus illness (6, 7). Another advantage of GS-441524 over remdesivir is the proposed reduced liver toxicity enabling dose escalation to ensure effective treatment of systemic SARS-CoV-2 infection (6). Thus, we propose trialing GS-441524 as a treatment option for pediatric MIS-C patients by effectively eradicating persisting intestinal SARS-CoV-2 infection.

References:

  1. Yonker LM et al. Multisystem inflammatory syndrome in children is driven by zonulin-dependent loss of gut mucosal barrier [published online May 25, 2021]. J Clin Invest. https://doi:10.1172/JCI149633
  2. Yan VC, Muller FL. Advantages of the Parent Nucleoside GS-441524 over Remdesivir for Covid-19 Treatment. ACS Med Chem Lett. 2020;11(7):1361-1366.
  3. Pedersen NC, et al. Efficacy and safety of the nucleoside analog GS-441524 for treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg. 2019;21(4):271-281.
  4. Addie DD, et al. Oral Mutian®X stopped faecal feline coronavirus shedding by naturally infected cats. Res Vet Sci. 2020;130:222-229.
  5. Alberer M, von Both U. Cats and kids: how a feline disease may help us unravel COVID-19 associated paediatric hyperinflammatory syndrome. Infection. 2021;49(1):191-193.
  6. Yan VC, et al. Pharmacokinetics of Orally Administered GS-441524 in Dogs [preprint]. https://doi.org/10.1101/2021.02.04.429674. Posted on bioRxiv May 31, 2021.
  7. Xie, J, Wang, Z. Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An in vitro and in vivo DMPK assessment [published online March 22, 2021]. Acta Pharmaceutica Sinica B. https://doi.org/10.1016/j.apsb.2021.03.028

Advertisement