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Varicella-zoster virus hijacks the type I interferon response and antigen presentation pathways in matured hiPSC-derived neurospheroids

ABSTRACT: Varicella-zoster virus (VZV) encephalitis and meningitis are potential central nervous system (CNS) complications following primary VZV infection or reactivation. With innate immune signalling, and more specifically type I interferon (IFN) signalling, being an important first line cellular defence mechanism against VZV infection, we here investigated the triggering of innate immune responses in a human CNS-like environment. For this, we established and characterised a 5-month matured hiPSC-derived neurospheroid (NSPH) model containing TuJ1+ MAP2+ NeuN+ neurons and GFAP+ S100b+ AQP4+ CD49f+ astrocytes. Immune competence of these NSPHs was demonstrated by secretion of IL-6 and CXCL10 following stimulation with a cocktail of pro-inflammatory stimuli. Subsequently, NSPHs were infected with reporter strains of VZV (eGFP-ORF23 VZV) and Sendai virus (eGFP SeV). Live cell and immunocytochemical analyses demonstrated VZV infection within NSPHs, while SeV infection was limited to the outer NSPH border. Next, a transcript-level immune profiling was performed using NanoString technology to explore innate immune signatures of virus-infected NSPHs. While SeV-infected NSPHs displayed a clear Type I IFN response, in VZV-infected NSPHs no Type I IFN response was activated. Even more, in the latter a strong suppression of genes related to IFN signalling and antigen presentation was noted. Validating these opposite immune signatures in VZV- and SeV-infected NSPHs, cytokine profiling of NSPH supernatant revealed increased secretion of IL6 and CXCL10 by SeV-infected NSPHs, but not by VZV-infected NSPHs. Similarly, immunocytochemical analysis demonstrated upregulation of type I IFN activated anti-viral proteins Mx1, IFIT2 and ISG15 in SeV-infected NSPHs, but not in VZV-infected NSPHs. Furthermore, CD74, a key part of the MHC class II antigen presentation pathway was found to be suppressed in VZV-infected NSPHs. Finally, even though VZV-infection seems to be immunologically ignored in NSPHs, its presence does result in the formation of stress granules throughout the entire NSPH. Concluding, in this study we demonstrate that 5-month matured hiPSC-derived NSPHs display functional innate immune reactivity towards SeV infection, as well as their capability to recapitulate the strong immune evasive behaviour of VZV. Subsequently, this NSPH model has the potential to study viral neuro-immune responses and evasion strategies in a human CNS-like environment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273529 | GEO | 2024/08/02

REPOSITORIES: GEO

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Project description:The major inducible 70 kDa heat shock protein (hsp70) is host protective in a mouse model of measles virus (MeV) brain infection. Transgenic constitutive expression of hsp70 in neurons, the primary target of MeV infection, abrogates neurovirulence in neonatal H-2d congenic C57BL/6 mice. A significant level of protection is retained after depletion of T lymphocytes, implicating innate immune mechanisms. Focus of the present work was to elucidate the basis for hsp70-dependent innate immunity using this model. Transcriptome analysis of brains from transgenic (TG) and non-transgenic (NT) mice 5 days after infection identified type 1 interferon (IFN) signaling and macrophage activation/antigen presentation as the main differences linked to survival. The pivotal role for type 1 IFN in hsp70-mediated protection was demonstrated in mice with a genetically disrupted type 1 IFN receptor (IFNAR-/-), where IFNAR-/- eliminated the difference in survival between TG and NT mice. Brain macrophages, not neurons, are the predominant source of type 1 IFN in the virus-infected brain, and in vitro studies provided a mechanistic basis by which MeV-infected neurons can induce IFN-β in uninfected microglia in an hsp70-dependent manner. MeV infection induced extracellular release of hsp70 from mouse neuronal cells that constitutively express hsp70, and extracellular hsp70 induced IFN-β transcription in mouse microglial cells through Toll-like receptors 2 and 4. Collectively, results support a novel axis of type 1 IFN-dependent antiviral immunity in the virus-infected brain that is driven by hsp70. Hsp70 expression in mice enhances gene expression related to antiviral immune response against MeV neurovirulence. We performed microarrays on whole brain tissues in mice to obtain an unbiased picture of how hsp70 alters host innate responses to viral infection. Hsp70-overexpressing transgenic (TG) and non-transgenic (NT) mice were infected with MeV intracranially, and total brain mRNA harvested at 5 and 10 days post infection (d.p.i.) was analyzed, sampling the hemisphere opposite the side of viral inoculation. Analysis includes 6 groups: infected TG at 5 d.p.i. (n=4), infected TG at 10 d.p.i. (n=5), infected NT at 5 d.p.i. (n=4), infected NT at 10 d.p.i. (n=5), uninfected TG at 5 d.p.i. (n=4), and uninfected NT at 5 d.p.i. (n=4).

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Varicella-zoster virus hijacks the type I interferon response and antigen presentation pathways in matured hiPSC-derived neurospheroids

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