Notch1-CD22-Dependent Immune Dysregulation in the SARS-CoV2-Associated Multisystem Inflammatory Syndrome in Children.
Talal A ChatilaMehdi BenamarQian ChenJanet ChouAmelie JuléRafik BoudraPaola ContiniElena CrestaniMuyun WangJason FongPeggy LaiShira RockwitzPui Y LeeTsz Man Fion ChanEkin Zeynep AltunEda KepenekliElif Karakoc-AydinerAhmet OzenPerran BoranFatih AygunPinar OnalAyse Ayzit Kilinc SakalliHaluk CokugrasMetin GelmezFatma ÖktelikEsin Aktaş CetinYuelin ZhongMaria TaylorKatherine IrbyNatasha HalasaSara SignaIgnazia PrigioneMarco GattornoNicola CotugnoDonato AmodioRaif GehaMary Beth SonJane W NewburgerPankaj AgrawalStefano VolpiPaolo PalmaAyca KiykimAdrienne G RandolphGunnur DenizSafa BarışRaffaele De PalmaKlaus Schmitz-AbeLouis-Marie CharbonnierLauren A HendersonPublished in: Research square (2022)
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 outcome were previously correlated with Notch4 expression on regulatory T (Treg) cells, here we show that the Treg cells in MIS-C are destabilized in association with increased Notch1 expression. Genetic analysis revealed that MIS-C patients were enriched in rare deleterious variant impacting inflammation and autoimmunity pathways, including dominant negative mutations in the Notch1 regulators NUMB and NUMBL . Notch1 signaling in Treg cells induced CD22, leading to their destabilization in an mTORC1 dependent manner and to the promotion of systemic inflammation. These results establish a Notch1-CD22 signaling axis that disrupts Treg cell function in MIS-C and point to distinct immune checkpoints controlled by individual Treg cell Notch receptors that shape the inflammatory outcome in SARS-CoV-2 infection.
Keyphrases
- sars cov
- induced apoptosis
- oxidative stress
- cell proliferation
- cell cycle arrest
- respiratory syndrome coronavirus
- liver failure
- end stage renal disease
- young adults
- coronavirus disease
- chronic kidney disease
- drug induced
- single cell
- stem cells
- ejection fraction
- transcription factor
- cell death
- respiratory failure
- long non coding rna
- mesenchymal stem cells
- peritoneal dialysis
- bone marrow
- aortic dissection
- high glucose
- cell therapy
- patient reported
- stress induced