Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling

Lint, Allison L. van; Murawski, Matthew R.; Goodbody, Rory; Severa, Martina; Fitzgerald, Katherine A.; Finberg, Robert W.; Knipe, David M.; Kurt-Jones, Evelyn A.

doi:10.1128/jvi.00063-10

Cited by 125 publications

(121 citation statements)

References 65 publications

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“…iii) In principle, STING is a component of the host innate defenses against exogenous DNA, and its function has been linked to activation of IRF3 and NF-κB (13)(14)(15). Numerous studies have shown that wild-type HSV-1 is fully competent in blocking the activation of IRF3 and NF-κB (10,25,26). Nevertheless, it came as a surprise that wild-type HSV-1 replicated better in HEL cells that had been depleted of STING.…”

Section: Discussionmentioning

confidence: 99%

HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation

Kalamvoki

Roizman

2014

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

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STING (stimulator of IFN genes) activates the IFN pathway in response to cytosolic DNA. Knockout of STING in mice was reported to exacerbate the pathogenicity of herpes simplex virus 1 (HSV-1). Here we report the following: (i) STING is stable in cancer-derived HEp-2 or HeLa cells infected with wild-type HSV-1 but is degraded in cells infected with mutants lacking the genes encoding functional infected cell protein 0 (ICP0), ICP4, or the US3 protein kinase (US3-PK). In HEp-2 cells, depletion of STING by shRNA results in a decrease in the yields of wild-type or ΔICP0 viruses. (ii) STING is stable throughout infection with either wild-type or ICP0 mutant viruses in human embryonic lung cells (HEL) or HEK293T cells derived from normal tissues. In these cells, depletion of STING results in higher yields of both wild-type and ΔICP0 viruses. (iii) The US3-PK is also required for stabilization of IFI16, a nuclear DNA sensor. However, the stability of IFI16 does not correlate positively or negatively with that of STING. IFI16 is stable in STING-depleted HEL cells infected with wild-type virus. In contrast to HEL cells, IFI16 was undetectable in STING-depleted HEp-2 cells, and hence the role of HSV-1 in maintaining IFI16 could not be ascertained. The results indicate that in HSV-1-infected cells the stability of IFI16 and the function and stability of STING are dependent on cell derivation, the functional integrity of ICP0, and US3-PK, an indication that in wild-type virus-infected cells both proteins are actively stabilized. In HEp-2 cells, the stability of IFI16 requires STING.innate immunity | cell transformation T he studies described in this report stem from two observations. First, a voluminous literature singles out the infected cell protein 0 (ICP0) as the major herpes simplex virus 1 (HSV-1) protein dedicated to defeating host responses to infection (1). Many of the functions of ICP0 designed to defeat host responses are executed by direct interaction between ICP0 and host proteins (2-8). In some instances, a plausible connection is apparent but no physical contact between ICP0 and the host effector protein is demonstrable (9, 10). Thus, ICP0 is associated with blocking the activation of IRF3 although a physical interaction between ICP0 and IRF3 has not been reported (10). One hypothesis that could explain such observations is that ICP0 interacts with the partners of the targeted protein rather than the target itself.Second, ICP0 accumulates during the first phase of the replicative cycle in the nucleus in which it performs multiple functions to enable efficient replication. Sometime between 5 and 9 h after exposure of cells to virus and depending on cell line, functional integrity of ICP0, and the amount of foreign DNA introduced into the cell, etc., ICP0 disappears from the nucleus and accumulates in the cytoplasm (11, 12). Several functions of ICP0 linked to physical interactions with cytoplasmic proteins have been described. Thus, ICP0 interacts with EF-1δ and enhances translation efficiency and with CIN85 t...

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Section: Discussionmentioning

confidence: 99%

HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation

Kalamvoki

Roizman

2014

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

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“…lated, and both can establish latency in sensory ganglia and recurrently reactivate to cause diseases, but they exhibit substantial differences in latency and reactivation patterns (75). A large number of studies have demonstrated that HSV-1 evolved multiple countermeasures to subvert the production of type I IFNs (67,71,(76)(77)(78)(79)(80). However, apart from the report that HSV-2 virion host shutoff (vhs) protein can suppress IFN-b expression (81), current understanding of HSV-2 immune evasion against the production of type I IFNs is limited.…”

Section: Discussionmentioning

confidence: 99%

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

Zhang

Liu

Wang

et al. 2015

The Journal of Immunology

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HSV-2 is the major cause of genital herpes, and its infection increases the risk of HIV-1 acquisition and transmission. After initial infection, HSV-2 can establish latency within the nervous system and thus maintains lifelong infection in humans. It has been suggested that HSV-2 can inhibit type I IFN signaling, but the underlying mechanism has yet to be determined. In this study, we demonstrate that productive HSV-2 infection suppresses Sendai virus (SeV) or polyinosinic-polycytidylic acid-induced IFN-β production. We further reveal that US1, an immediate-early protein of HSV-2, contributes to such suppression, showing that US1 inhibits IFN-β promoter activity and IFN-β production at both mRNA and protein levels, whereas US1 knockout significantly impairs such capability in the context of HSV-2 infection. US1 directly interacts with DNA binding domain of IRF-3, and such interaction suppresses the association of nuclear IRF-3 with the IRF-3 responsive domain of IFN-β promoter, resulting in the suppression of IFN-β promoter activation. Additional studies demonstrate that the 217–414 aa domain of US1 is critical for the suppression of IFN-β production. Our results indicate that HSV-2 US1 downmodulates IFN-β production by suppressing the association of IRF-3 with the IRF-3 responsive domain of IFN-β promoter. Our findings highlight the significance of HSV-2 US1 in inhibiting IFN-β production and provide insights into the molecular mechanism by which HSV-2 evades the host innate immunity, representing an unconventional strategy exploited by a dsDNA virus to interrupt type I IFN signaling pathway.

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“…HSV-1 has also evolved mechanisms to downregulate IFN expression, for example, via IRF3 degradation mediated by immediate early infected cell protein 0 (ICP0), which prevents accumulation of IFN-β (65). In addition, expression of ICP0 alone can prevent TLR2-dependent NF-κB activation in cell culture, which suggests that the virus downregulates the immune response at several points in the inflammatory pathway (66). CD4 + T cells are an important source of IFN-γ, have cytotoxic effector activity for HSV-infected cells, and localize to HSV-2 genital lesions (50).…”

Section: Hsv-2 Transmission Dynamicsmentioning

confidence: 99%

HSV-2: in pursuit of a vaccine

Johnston

Koelle²,

Wald³

2011

J. Clin. Invest.

127

111

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Herpes simplex virus type 2 (HSV-2) is one of the most prevalent sexually transmitted infections worldwide. In addition to recurrent genital ulcers, HSV-2 causes neonatal herpes, and it is associated with a 3-fold increased risk for HIV acquisition. Although many HSV-2 vaccines have been studied in animal models, few have reached clinical trials, and those that have been tested in humans were not consistently effective. Here, we review HSV-2 pathogenesis, with a focus on novel understanding of mucosal immunobiology of HSV-2, and vaccine efforts to date, in an attempt to stimulate thinking about future directions for development of effective prophylactic and therapeutic HSV-2 vaccines.

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Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling

Cited by 125 publications

References 65 publications

HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation

HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation

HSV-2 Immediate-Early Protein US1 Inhibits IFN-β Production by Suppressing Association of IRF-3 with IFN-β Promoter

HSV-2: in pursuit of a vaccine

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