Herpes Simplex Virus 1 Has Multiple Mechanisms for Blocking Virus-Induced Interferon Production

Melroe, Gregory T.; DeLuca, Neal A.; Knipe, David M.

doi:10.1128/jvi.78.16.8411-8420.2004

Cited by 169 publications

(194 citation statements)

References 73 publications

(74 reference statements)

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“…To examine whether cGAS depletion resulted in reduced innate immune signaling in response to HSV-1 infection, we infected STING-, IFI16-, or cGAS-depleted cells with one of two HSV-1 recombinant viruses, d109 (18) or 7134 (19), which show enhanced antiviral signaling because of the absence of the known viral inhibitors of the innate immune response (8,(20)(21)(22). We examined the induction of three cellular genes, ISG54, IFNβ, and IL-6, which are differentially regulated by specific transcription factors upon activation of innate signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Orzalli

Broekema

Diner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Interferon γ-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling.protein-protein interactions | DNA sensing | innate immunity | virus-host interactions T he innate immune response is a crucial component of host immunity and is the first line of defense against microbial pathogens, including bacteria and viruses. The initial events during infection of a host cell induce intracellular signaling pathways, resulting in the production of proinflammatory cytokines and IFNs. These effector molecules activate an antiviral state in neighboring cells and recruit immune cells to promote clearance of infection. Viral nucleic acids are potent activators of these signaling pathways and are recognized by a subset of host cell pattern recognition receptors (PRRs). These PRRs include the membrane-bound Toll-like receptors, the cytosolic RIG-Ilike receptors, and a broad class of putative DNA sensors, which include both cytosolic and nuclear proteins (1).Unlike viral RNAs, which are distinct from cellular RNAs and therefore recognized by intracellular PRRs, DNA genomes of viruses that replicate in the nucleus are thought to be chemically and structurally similar to host DNA (2-4). It was therefore generally accepted that viral DNA sensing was limited to the cytoplasm where aberrant DNA accumulation would be perceived as "foreign." However, this dogma has recently been challenged by the identification of DNA-sensing pathways that are active in the nucleus. The Pyrin and HIN-containing interferon γ-inducible protein 16 (IFI16) protein, initially described as a cytosolic DNA sensor (5), has been demonstrated to be nuclear in many cells and to promote the activation of inflammasomes (6, 7) and production of IFNs (8, 9) in response to herpesvirus infection. These initial studies involved short-term siRNA depletion of IFI16; in addition, a recent study showed that long-term knockdown of IFI16 expression led to abrogated IFN responses to not only DNA viruses, such as herpes simplex virus (HSV), but also RNA viruses, such as Sendai virus (10).cGMP-AMP synthase (cGAS) was also ident...

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Section: Resultsmentioning

confidence: 99%

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Orzalli

Broekema

Diner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

212

225

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“…Rotavirus non-structural protein 1 (NSP1) also targets IRF-3 for degradation (Graff et al, 2007), as well as IRF-5 and IRF-7 (Barro & Patton, 2007). Similarly, ICP0 of HSV-1 inhibits IRF-3 and IRF-7 (Lin et al, 2004a;Melroe et al, 2004), reportedly by recruiting activated IRF-3 and CBP/p300 to nuclear structures away from host chromatin (Melroe et al, 2007). In contrast, it appears that bovine herpesvirus 1 (BHV-1) bICP0 targets IRF-3 for degradation (Saira et al, 2007).…”

Section: General Considerations Of How Viruses Evade the Ifn Responsementioning

confidence: 99%

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Randall

Goodbourn

2008

Journal of General Virology

1,389

1,420

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The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer. Biology of the interferon systemThe interferons (IFNs) are a group of secreted cytokines that elicit distinct antiviral effects. They are grouped into three classes called type I, II and III IFNs, according to their amino acid sequence. Type I IFNs (discovered in 1957;Isaacs & Lindenmann, 1957) comprise a large group of molecules; mammals have multiple distinct IFN-a genes (13 in man), one to three IFN-b genes (one in man) and other genes, such as IFN-v, -e, -t, -d and -k. The IFN-a and -b genes are induced directly in response to viral infection, whereas IFN-v, -e, -d and -k play less well-defined roles, such as regulators of maternal recognition in pregnancy. Thus, rather than use the term 'type I IFN', we will use IFN-a/b when referring to the virally induced cytokines. Although the multigenic nature of IFN-a has been known for over 20 years, the significance of this is still debatedi.e. whether these genes are expressed differentially in distinct cell types, whether they are inducible by different types of viruses or whether they are functionally specialized (Brideau-Andersen et al., 2007). For the rest of this review, we will not distinguish between IFN-a subtypes. Type III IFNs have been described more recently and comprise IFNl1, -l2 and -l3, also referred to as IL-2...

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“…Accordingly, expression of ICP0 inhibits the induction of antiviral programs mediated by IRF3 or IRF7 (21)(22)(23). However, although ICP0 negatively regulates IFN-␤ expression, it is not essential for this effect (24). In HSV-infected human macrophages or dendritic cells, an immediate early protein ICP27 is required to suppress cytokine induction involving IRF3 (25).…”

mentioning

confidence: 99%

Control of TANK-binding Kinase 1-mediated Signaling by the γ134.5 Protein of Herpes Simplex Virus 1

Verpooten

Hou

et al. 2009

Journal of Biological Chemistry

173

187

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Herpes Simplex Virus 1 Has Multiple Mechanisms for Blocking Virus-Induced Interferon Production

Cited by 169 publications

References 73 publications

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures

Control of TANK-binding Kinase 1-mediated Signaling by the γ134.5 Protein of Herpes Simplex Virus 1

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