20.500.12556/DiRROS-21153 Varicella-zoster virus recapitulates its immune evasive behaviour in matured hiPSC-derived neurospheroids Varicella-zoster virus (VZV) encephalitis and meningitis are potential central nervous system (CNS) complications following primary VZV infection or reactivation. With Type-I interferon (IFN) signalling being an important first line cellular defence mechanism against VZV infection by the peripheral tissues, we here investigated the triggering of innate immune responses in a human neural-like environment. For this, we established and characterised 5-month matured hiPSC-derived neurospheroids (NSPHs) containing neurons and astrocytes. Subsequently, NSPHs were infected with reporter strains of VZV (VZVeGFP-ORF23) or Sendai virus (SeVeGFP), with the latter serving as an immune-activating positive control. Live cell and immunocytochemical analyses demonstrated VZVeGFP-ORF23 infection throughout the NSPHs, while SeVeGFP infection was limited to the outer NSPH border. Next, NanoString digital transcriptomics revealed that SeVeGFP-infected NSPHs activated a clear Type-I IFN response, while this was not the case in VZVeGFP-ORF23-infected NSPHs. Moreover, the latter displayed a strong suppression of genes related to IFN signalling and antigen presentation, as further demonstrated by suppression of IL-6 and CXCL10 production, failure to upregulate Type-I IFN activated anti-viral proteins (Mx1, IFIT2 and ISG15), as well as reduced expression of CD74, a key-protein in the MHC class II antigen presentation pathway. Finally, even though VZVeGFP-ORF23-infection seems to be immunologically ignored in NSPHs, its presence does result in the formation of stress granules upon long-term infection, as well as disruption of cellular integrity within the infected NSPHs. Concluding, in this study we demonstrate that 5-month matured hiPSC-derived NSPHs display functional innate immune reactivity towards SeV infection, and have the capacity to recapitulate the strong immune evasive behaviour towards VZV. interferon signalling neurospheroids antigen presentation stress granules structural integrity true false true Frontiers Švica Angleški jezik Ni določen © 2024 Govaerts, Van Breedam, De Beuckeleer, Goethals, D’Incal, Di Stefano, Van Calster, Buyle-Huybrecht, Boeren, De Reu, Paludan, Thiry, Lebrun, Sadzot-Delvaux, Motaln, Rogelj, Van Weyenbergh, De Vos, Vanden Berghe, Ogunjimi, Delputte and Ponsaerts. Neznano 2025-01-08 12:37:14 2025-01-08 12:37:15 2025-01-09 03:38:02 0000-00-00 00:00:00 2024 0 0 Nasl. z nasl. zaslona; Soavtorja iz Slovenije: Helena Motaln, Boris Rogelj; Opis vira z dne 16. 9. 2024; str. 1-19 Vol 15 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 2024-07-03 2024-08-13 2024-09-16 57 1664-3224 10.3389/fimmu.2024.1458967 207650563 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1458967/full 1 ea0f242c-cdb4-11ef-ba3f-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=30006 RAZ_Govaerts_Jonas_2024.pdf RAZ_Govaerts_Jonas_2024.pdf 1 6F762187F62C8C9389805B6D77E69FAC 16d8ec638a8f192177882eac6a471c37bda83eb3cdefc5acd71783218f8c5027 2470fbcd-cdba-11ef-ba3f-001a4af901a5 https://dirros.openscience.si/Dokument.php?lang=slv&id=30014 Institut Jožef Stefan 0 0 0