In:
Frontiers in Immunology, Frontiers Media SA, Vol. 15 ( 2024-9-16)
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 (VZV eGFP-ORF23 ) or Sendai virus (SeV eGFP ), with the latter serving as an immune-activating positive control. Live cell and immunocytochemical analyses demonstrated VZV eGFP-ORF23 infection throughout the NSPHs, while SeV eGFP infection was limited to the outer NSPH border. Next, NanoString digital transcriptomics revealed that SeV eGFP -infected NSPHs activated a clear Type-I IFN response, while this was not the case in VZV eGFP-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 VZV eGFP-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.
Type of Medium:
Online Resource
ISSN:
1664-3224
DOI:
10.3389/fimmu.2024.1458967
DOI:
10.3389/fimmu.2024.1458967.s001
DOI:
10.3389/fimmu.2024.1458967.s002
DOI:
10.3389/fimmu.2024.1458967.s003
DOI:
10.3389/fimmu.2024.1458967.s004
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2024
detail.hit.zdb_id:
2606827-8