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Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection.

ABSTRACT: Nuclear factor kappa B (NF-?B) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-?B and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-?B is essential for resistance to ectromelia virus (ECTV), a mouse orthopoxvirus related to the virus causing human smallpox. Additionally, an ECTV mutant lacking an NF-?B inhibitor activates NF-?B more effectively in vivo, resulting in increased proinflammatory molecule transcription in uninfected cells and organs and decreased viral replication. Unexpectedly, NF-?B activation compensates for genetic defects in the T1-IFN pathway, such as a deficiency in the IRF7 transcription factor, resulting in virus control. Thus, overlap between the T1-IFN and NF-?B pathways allows the host to overcome genetic or pathogen-induced deficiencies in T1-IFN and survive an otherwise lethal poxvirus infection. These findings may also explain why some pathogens target both pathways to cause disease.

SUBMITTER: Rubio D

PROVIDER: S-EPMC3688842 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection.

Rubio Daniel D Xu Ren-Huan RH Remakus Sanda S Krouse Tracy E TE Truckenmiller Mary Ellen ME Thapa Roshan J RJ Balachandran Siddharth S Alcamí Antonio A Norbury Christopher C CC Sigal Luis J LJ

Cell host & microbe 20130601 6

Nuclear factor kappa B (NF-κB) and type 1 interferon (T1-IFN) signaling are innate immune mechanisms activated upon viral infection. However, the role of NF-κB and its interplay with T1-IFN in antiviral immunity is poorly understood. We show that NF-κB is essential for resistance to ectromelia virus (ECTV), a mouse orthopoxvirus related to the virus causing human smallpox. Additionally, an ECTV mutant lacking an NF-κB inhibitor activates NF-κB more effectively in vivo, resulting in increased pro ...[more]

PMID: 23768494

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Project description:Persistent high-risk human papillomavirus (HPV) infection is the major causal factor in cervical and other anogenital cancers. Because there are currently no therapeutics capable of preventing neoplastic progression of HPV infections, understanding the mechanisms of HPV-mediated persistence, including immune evasion, is a major research priority. The multifunctional growth factor transforming growth factor beta (TGF?) has been shown to inhibit expression of early viral transcripts from cells harboring integrated HPV genomes or cells infected with retroviruses expressing HPV oncoproteins. However, the mechanism of TGF?-induced inhibition has not been fully defined. In this study, we have observed a previously uncharacterized ability of TGF? to repress the differentiation-induced upregulation of late HPV16 gene expression. In addition, interferon kappa (IFN-?), a keratinocyte-specific, constitutively expressed cytokine suppressed by differentiation, can be transcriptionally induced by TGF?1. TGF?-mediated IFN-? transcription only occurs in cells containing HPV16, and this is due to TGF?1-mediated reversal of HPV-induced methylation of the IFN-? promoter through active DNA demethylation mediated by thymine DNA glycosylase (TDG). This novel interaction between growth factor and innate immune signaling may shed light on the mechanisms of HPV persistence and how the virus manipulates both immune and growth factor signaling to promote its life cycle.IMPORTANCE Persistent infection by high-risk HPVs is the primary risk factor for development of HPV-induced cancers. Persistence involves viral evasion of the immune response, including the IFN response. HPV is also known to suppress TGF? signaling, which inhibits viral gene expression. Here, we show that the TGF? and IFN pathways are interrelated in the context of HPV16 infection through the upregulation of IFN-? by TGF?. The ability of TGF? to induce IFN-? promoter demethylation and transcriptional activation provides a new explanation for why HPV has evolved mechanisms to inhibit TGF? in infected cells.

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Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection.

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Crosstalk between the type 1 interferon and nuclear factor kappa B pathways confers resistance to a lethal virus infection.

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