Abstract
Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
Highlights
The intrinsic, innate, and adaptive arms of host immunity cooperatively supress the replication and spread of invading viral pathogens
We show that HIRA, a histone H3.3 chaperone, associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences in response to herpes simplex virus 1 (HSV-1) infection
The stable localization of HIRA at PML-NBs was only observed at comparatively late times post-infection (2–6 days; [17, 18]), which is atypical of intrinsic PML-NB host factors that silence viral gene expression from the outset of nuclear infection [9, 19, 27,28,29,30,31]
Summary
The intrinsic, innate, and adaptive arms of host immunity cooperatively supress the replication and spread of invading viral pathogens. Activation of Pattern Recognition Receptors (PRRs) by microbial specific Pathogen-Associated Molecular Patterns (PAMPs) leads to the induction of innate immune defences and the coordinated upregulation of a broad repertoire of host antiviral genes, principally cytokines (including interferons; IFNs) and interferon stimulated gene (ISG) products [3,4,5,6]. This induced immune response confers an enhanced antiviral state to limit virus spread and prime adaptive immune responses. Intrinsic host defences can inhibit the onset of HSV-1 lytic replication in restrictive cell types independently of the induction of innate immune defences [9, 37]
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