| Title: | Varicella-zoster virus recapitulates its immune evasive behaviour in matured hiPSC-derived neurospheroids |
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| Authors: | ID Govaerts, Jonas (Author)
ID Van Breedam, Elise (Author)
ID Motaln, Helena, Institut "Jožef Stefan" (Author)
ID Rogelj, Boris (Author)
ID Ponsaerts, Peter (Author) |
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| Files: |  URL - Source URL, visit https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1458967/full
 PDF - Presentation file, download (12,62 MB)
MD5: 6F762187F62C8C9389805B6D77E69FAC
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| Language: | English |
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| Typology: | 1.01 - Original Scientific Article |
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| Organization: |  IJS - Jožef Stefan Institute
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| Abstract: | 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. |
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| Keywords: | interferon signalling, neurospheroids, antigen presentation, stress granules, structural integrity |
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| Publication status: | Published |
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| Publication version: | Version of Record |
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| Submitted for review: | 03.07.2024 |
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| Article acceptance date: | 13.08.2024 |
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| Publication date: | 16.09.2024 |
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| Publisher: | Frontiers |
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| Year of publishing: | 2024 |
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| Number of pages: | str. 1-19 |
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| Numbering: | Vol 15 |
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| Source: | Švica |
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| PID: | 20.500.12556/DiRROS-21153  |
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| UDC: | 57 |
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| ISSN on article: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2024.1458967 |
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| COBISS.SI-ID: | 207650563 |
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| Copyright: | © 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. |
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| Note: | Nasl. z nasl. zaslona;
Soavtorja iz Slovenije: Helena Motaln, Boris Rogelj;
Opis vira z dne 16. 9. 2024;
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| Publication date in DiRROS: | 08.01.2025 |
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| Views: | 657 |
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| Downloads: | 418 |
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