Browsing by Author "Bondarev, Marina"

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    TGFβ links EBV to multisystem inflammatory syndrome in children
    (2025) Goetzke, Carl; Massou, Mona; Frischbutt, Stefan; Guerra, Gabriela; Ferreira, Marta; Heinrich, Frederik; Von Stuckra, Anne; Wisniewsk, Sebastian; Lich, Jan; Bondarev, Marina; Ehler, Lisa; Khaldi, Samira; Javouhe, Etienne; Pons, Sylvie; Trouillet, Sophie; Ozsurek, Yasemin; Zhang, Yu; Poli Harlowe, María Cecilia; Discepolo, Valentina; Lo Vecchio, Andrea; Sahin, Bengü; Verboom, Murielle; Hallenslebe, Michael; Heuhse, Anja; Astudillo, Camila; Espinosa, Yazmin; Vial, Maria Cecilia; Dobbs, Kerry; Delmont, Ottavia; Montealegre, Gina; Magliocco, Mary; Barron, Karyl; Danielson, Jeffrey; Petrov, Lev; Unterwalder, Nadine; Sawitzk,i Birgit; Matz, Mareen; Lehmann, Katrin; Gratop, Alexander; Von Bernuth, Horst; Burkhardt, Lisa; Wiese, Niklas; Peter, Lena; Schmueck, Michael; Amini, Leila; Maurer, Marcus; Roehmel, Jobst; Gewur, Benjamin; Yonker, Lael; Witkowsk, Mario; Kruglov, Andrey; Mall, Marcus; Su, Helen; Ozen, Seza; Radbruch, Andreas; Belot, Alexandre; Durek, Pawel; Kallinich, Tilmann; Mashregh, Mir-Farzin
    In a subset of children and adolescents, SARS-CoV-2 infection induces a severe acute hyperinflammatory shock1 termed multisystem inflammatory syndrome in children (MIS-C) at four to eight weeks after infection. MIS-C is characterized by a specific T cell expansion2 and systemic hyperinflammation3. The pathogenesis of MIS-C remains largely unknown. Here we show that acute MIS-C is characterized by impaired reactivation of virus-reactive memory T cells, which depends on increased serum levels of the cytokine TGFβ resembling those that occur during severe COVID-19 (refs. 4,5). This functional impairment in T cell reactivity is accompanied by the presence of TGFβ-response signatures in T cells, B cells and monocytes along with reduced antigen-presentation capabilities of monocytes, and can be reversed by blocking TGFβ. Furthermore, T cell receptor repertoires of patients with MIS-C exhibit expansion of T cells expressing TCRVβ21.3, resembling Epstein-Barr virus (EBV)-reactive T cell clones capable of eliminating EBV-infected B cells. Additionally, serum TGFβ in patients with MIS-C can trigger EBV reactivation, which is reversible with TGFβ blockade. Clinically, the TGFβ-induced defect in T cell reactivity correlates with a higher EBV seroprevalence in patients with MIS-C compared with age-matched controls, along with the occurrence of EBV reactivation. Our findings establish a connection between SARS-CoV-2 infection and COVID-19 sequelae in children, in which impaired T cell cytotoxicity triggered by TGFβ overproduction leads to EBV reactivation and subsequent hyperinflammation.

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