PML‐NB‐dependent type I interferon memory results in a restricted form of HSV latency

Suzich, Jon B.; Cuddy, Sean R; Baidas, Hiam; Dochnal, Sara; Ke, Eugene; Schinlever, Austin; Babnis, Aleksandra; Boutell, Chris; Cliffe, Anna R.

doi:10.15252/embr.202152547

Cited by 26 publications

(39 citation statements)

References 130 publications

(189 reference statements)

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“…Viral DNA and PML co-localize rapidly in cultured neurons of both murine and human origin (30,31,59,60), forming structures that have been called viral DNA containing PML-nuclear bodies (vDCP-NB) that are also DAXX/ATRX/SP100-positive in the absence of ICP0 expression. Neurons have PML-ND10 complexes, but recent work suggests ND10 form more cohesively when neurons are exposed to IFN-I, such as might occur when axons in peripherally infected tissues are exposed and there is subsequent signaling along the axon (61). The silenced viral genomes subsequently become enriched with characteristic heterochromatic histone modifications, such as histone H3 diand tri-methylated at lysine 9 (H3K9me2/3) and H3K27me3 (29,(62)(63)(64).…”

Section: Promyelocytic Leukemia Protein and The Nuclear Domain 10 Complexmentioning

confidence: 99%

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

et al. 2021

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Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen. HSV-1 genomes persist in trigeminal ganglia neuronal nuclei as chromatinized episomes, while epithelial cells are typically killed by lytic infection. Fluctuations in anti-viral responses, broadly defined, may underlay periodic reactivations. The ganglionic immune response to HSV-1 infection includes cell-intrinsic responses in neurons, innate sensing by several cell types, and the infiltration and persistence of antigen-specific T-cells. The mechanisms specifying the contrasting fates of HSV-1 in neurons and epithelial cells may include differential genome silencing and chromatinization, dictated by variation in access of immune modulating viral tegument proteins to the cell body, and protection of neurons by autophagy. Innate responses have the capacity of recruiting additional immune cells and paracrine activity on parenchymal cells, for example via chemokines and type I interferons. In both mice and humans, HSV-1-specific CD8 and CD4 T-cells are recruited to ganglia, with mechanistic studies suggesting active roles in immune surveillance and control of reactivation. In this review we focus mainly on HSV-1 and the TG, comparing and contrasting where possible observational, interventional, and in vitro studies between humans and animal hosts.

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Section: Promyelocytic Leukemia Protein and The Nuclear Domain 10 Complexmentioning

confidence: 99%

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

et al. 2021

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“…Suzich et al (2021) now elegantly demonstrate that the latent HSV genome can exist in multiple states with respect to reactivation that are a function of the presence of PML‐NBs. PML‐NBs have been shown to result in the deposition of histone H3.3 modified on lysine 9 by trimethylation (H3K9me3), and in the absence of PML, there is a shift versus H3K27me3 (Delbarre et al , 2017).…”

Section: Figure Multiple Types Of Hsv Latency Programmes Are Maintain...mentioning

confidence: 99%

New model integrates innate responses, PML‐NB formation, epigenetic control and reactivation from latency

Weller

DeLuca

2021

EMBO Reports

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The dynamic nature of interactions between invading viral pathogens and their hosts has fascinated scientists for several decades. The well‐known capacity of herpes simplex virus (HSV) to establish life‐long infections in humans reflects a dynamic balance between maintaining a latent state in which viral genomes are silenced and re‐entry into the lytic phase during reactivation. Silencing of the viral genome has been shown to be a function of innate immune signalling, intrinsic cellular antiviral mechanisms and epigenetic repression. Thus, although many important observations have been made identifying cellular processes that contribute to the repression of the viral genome and latency, the field has lacked an understanding of how these factors work together. In this issue of EMBO Reports, Suzich et al (2021) present convincing evidence that brings together individual observations into a cohesive model that explains many of these outstanding mysteries. Here, we will review the background data that lead to this outstanding piece of work.

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“…The upregulated IFN then signals the IFN receptors on the plasma membrane to activate the downstream Janus kinases (Jak)/signal transducers and activators of transcription (STAT) pathway, thereby inducing the expression of hundreds of interferon-stimulated genes (ISGs), which collectively establishes an antiviral state [2]. Type I IFN is not only crucial for HSV-1 clearance from non-neuronal cells, but its neuronal signaling also protects the host from HSV-1 replication and pathogenesis [3][4][5]. To overcome the antiviral state, HSV-1 has involved various strategies that evade or subvert the IFN response [6,7].…”

Section: Introductionmentioning

confidence: 99%

Host MOV10 is induced to restrict herpes simplex virus 1 lytic infection by promoting type I interferon response

et al. 2022

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Moloney leukemia virus 10 protein (MOV10) is an IFN-inducible RNA helicase implicated in antiviral activity against RNA viruses, yet its role in herpesvirus infection has not been investigated. After corneal inoculation of mice with herpes simplex virus 1 (HSV-1), we observed strong upregulation of both MOV10 mRNA and protein in acutely infected mouse trigeminal ganglia. MOV10 suppressed HSV-1 replication in both neuronal and non-neuronal cells, and this suppression required the N-terminus, but not C-terminal helicase domain of MOV10. MOV10 repressed expression of the viral gene ICP0 in transfected cells, but suppressed HSV-1 replication independently of ICP0. MOV10 increased expression of type I IFN in HSV-1 infected cells with little effect on IFN downstream signaling. Treating the cells with IFN-α or an inhibitor of the IFN receptor eliminated MOV10 suppression of HSV-1 replication. MOV10 enhanced IFN production stimulated by cytoplasmic RNA rather than DNA. IKKε co-immunoprecipitated with MOV10 and was required for MOV10 restriction of HSV-1 replication. Mass spectrometry identified ICP27 as a viral protein interacting with MOV10. Co-immunoprecipitation results suggested that this interaction depended on the RGG box of ICP27 and both termini of MOV10. Overexpressed ICP27, but not its RGG-Box deletion mutant, rendered MOV10 unable to regulate HSV-1 replication and type I IFN production. In summary, MOV10 is induced to restrict HSV-1 lytic infection by promoting the type I IFN response through an IKKε-mediated RNA sensing pathway, and its activity is potentially antagonized by ICP27 in an RGG box dependent manner.

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PML‐NB‐dependent type I interferon memory results in a restricted form of HSV latency

Cited by 26 publications

References 130 publications

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

Local Immune Control of Latent Herpes Simplex Virus Type 1 in Ganglia of Mice and Man

New model integrates innate responses, PML‐NB formation, epigenetic control and reactivation from latency

Host MOV10 is induced to restrict herpes simplex virus 1 lytic infection by promoting type I interferon response

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