Jonas Govaerts (Author), Elise Van Breedam (Author), Helena Motaln (Author), Boris Rogelj (Author), Peter Ponsaerts (Author)

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.

Keywords

interferon signalling;neurospheroids;antigen presentation;stress granules;structural integrity;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: IJS - Jožef Stefan Institute
Publisher: Frontiers
UDC: 57
COBISS: 207650563 Link will open in a new window
ISSN: 1664-3224
Views: 27
Downloads: 11
Average score: 0 (0 votes)
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Other data

Secondary keywords: Virus noric;Interferoni;
Source comment: Nasl. z nasl. zaslona; Soavtorja iz Slovenije: Helena Motaln, Boris Rogelj; Opis vira z dne 16. 9. 2024;
Pages: str. 1-19
Issue: ǂVol ǂ15
Chronology: 2024
DOI: 10.3389/fimmu.2024.1458967
ID: 25646593