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The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

ABSTRACT: Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathways, including dominant-negative mutations in the Notch1 regulators NUMB and NUMBL leading to Notch1 upregulation. Notch1 signaling in Tregs induced CD22, leading to their destabilization in a mTORC1-dependent manner and to the promotion of systemic inflammation. These results identify a Notch1/CD22 signaling axis that disrupts Treg function in MIS-C and point to distinct immune checkpoints controlled by individual Treg Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.

SUBMITTER: Benamar M

PROVIDER: S-EPMC9797337 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Benamar Mehdi M Chen Qian Q Chou Janet J Julé Amélie M AM Boudra Rafik R Contini Paola P Crestani Elena E Lai Peggy S PS Wang Muyun M Fong Jason J Rockwitz Shira S Lee Pui P Chan Tsz Man Fion TMF Altun Ekin Zeynep EZ Kepenekli Eda E Karakoc-Aydiner Elif E Ozen Ahmet A Boran Perran P Aygun Fatih F Onal Pinar P Sakalli Ayse Ayzit Kilinc AAK Cokugras Haluk H Gelmez Metin Yusuf MY Oktelik Fatma Betul FB Cetin Esin Aktas EA Zhong Yuelin Y Taylor Maria Lucia ML Irby Katherine K Halasa Natasha B NB Mack Elizabeth H EH Signa Sara S Prigione Ignazia I Gattorno Marco M Cotugno Nicola N Amodio Donato D Geha Raif S RS Son Mary Beth MB Newburger Jane J Agrawal Pankaj B PB Volpi Stefano S Palma Paolo P Kiykim Ayca A Randolph Adrienne G AG Deniz Gunnur G Baris Safa S De Palma Raffaele R Schmitz-Abe Klaus K Charbonnier Louis-Marie LM Henderson Lauren A LA Chatila Talal A TA

The Journal of clinical investigation 20230103 1

Multisystem inflammatory syndrome in children (MIS-C) evolves in some pediatric patients following acute infection with SARS-CoV-2 by hitherto unknown mechanisms. Whereas acute-COVID-19 severity and outcomes were previously correlated with Notch4 expression on Tregs, here, we show that Tregs in MIS-C were destabilized through a Notch1-dependent mechanism. Genetic analysis revealed that patients with MIS-C had enrichment of rare deleterious variants affecting inflammation and autoimmunity pathway ...[more]

PMID: 36282598

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Project description:Multisystem inflammatory syndrome in children (MIS-C) is a febrile pediatric inflammatory disease that may develop weeks after initial SARS-CoV-2 infection or exposure. MIS-C involves systemic hyperinflammation and multiorgan involvement, including severe cardiovascular, gastrointestinal (GI) and neurological symptoms. Some clinical attributes of MIS-C-such as persistent fever, rashes, conjunctivitis and oral mucosa changes (red fissured lips and strawberry tongue)-overlap with features of Kawasaki disease (KD). In addition, MIS-C shares striking clinical similarities with toxic shock syndrome (TSS), which is triggered by bacterial superantigens (SAgs). The remarkable similarities between MIS-C and TSS prompted a search for SAg-like structures in the SARS-CoV-2 virus and the discovery of a unique SAg-like motif highly similar to a Staphylococcal enterotoxin B (SEB) fragment in the SARS-CoV-2 spike 1 (S1) glycoprotein. Computational studies suggest that the SAg-like motif has a high affinity for binding T-cell receptors (TCRs) and MHC Class II proteins. Immunosequencing of peripheral blood samples from MIS-C patients revealed a profound expansion of TCR β variable gene 11-2 (TRBV11-2), which correlates with MIS-C severity and serum cytokine levels, consistent with a SAg-triggered immune response. Computational sequence analysis of SARS-CoV-2 spike further identified conserved neurotoxin-like motifs which may alter neuronal cell function and contribute to neurological symptoms in COVID-19 and MIS-C patients. Additionally, autoantibodies are detected during MIS-C, which may indicate development of post-SARS-CoV-2 autoreactive and autoimmune responses. Finally, prolonged persistence of SARS-CoV-2 RNA in the gut, increased gut permeability and elevated levels of circulating S1 have been observed in children with MIS-C. Accordingly, we hypothesize that continuous and prolonged exposure to the viral SAg-like and neurotoxin-like motifs in SARS-CoV-2 spike may promote autoimmunity leading to the development of post-acute COVID-19 syndromes, including MIS-C and long COVID, as well as the neurological complications resulting from SARS-CoV-2 infection.

Dataset Information

The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Publications

The Notch1/CD22 signaling axis disrupts Treg function in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Similar Datasets

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