Innate immune activation of NFκB and its antagonism by poxviruses

Brady, Gareth; Bowie, Andrew

doi:10.1016/j.cytogfr.2014.07.004

Cited by 43 publications

(35 citation statements)

References 103 publications

(119 reference statements)

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“…Nuclear factor-κB (NF-κB) is one of the most important transcription factors involved in immune signaling (Ghosh et al, 1998; Lee and Kim, 2007). Accordingly, NF-κB is frequently targeted by many different viruses, including HPV (Brady and Bowie, 2014; Correia et al, 2013; Qu and Lemon, 2010; Vandermark et al, 2012). High-risk HPVs decrease K310 acetylation of NF-κB in keratinocytes by enhancing IFN related developmental regulator 1 (IFRD1) expression, resulting in downregulation of proinflammatory cytokines (Tummers et al, 2015) (Fig.…”

Section: Immune Evasion By Altering Host Gene Expressionmentioning

confidence: 99%

Evasion of host immune defenses by human papillomavirus

2017

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A majority of human papillomavirus (HPV) infections are asymptomatic and self-resolving in the absence of medical interventions. Various innate and adaptive immune responses, as well as physical barriers, have been implicated in controlling early HPV infections. However, if HPV overcomes these host immune defenses and establishes persistence in basal keratinocytes, it becomes very difficult for the host to eliminate the infection. The HPV oncoproteins E5, E6, and E7 are important in regulating host immune responses. These oncoproteins dysregulate gene expression, protein-protein interactions, posttranslational modifications, and cellular trafficking of critical host immune modulators. In addition to the HPV oncoproteins, sequence variation and dinucleotide depletion in papillomavirus genomes has been suggested as an alternative strategy for evasion of host immune defenses. Since anti-HPV host immune responses are also considered to be important for antitumor immunity, immune dysregulation by HPV during virus persistence may contribute to immune suppression essential for HPV-associated cancer progression. Here, we discuss cellular pathways dysregulated by HPV that allow the virus to evade various host immune defenses.

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Section: Immune Evasion By Altering Host Gene Expressionmentioning

confidence: 99%

Evasion of host immune defenses by human papillomavirus

2017

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“…These proteins then further evolve by refinement of their inhibitory activity through gradual mutation over long periods of virus-host evolution (2). Although the discovery and characterization of such poxvirus inhibitory proteins in nonhuman adapted poxviruses like vaccinia virus (VACV) have been highly informative in defining host-virus interactions and uncovering novel aspects of innate immunity (3), only a small number of these inhibitors have been described for the only known extant human-adapted poxvirus, molluscum contagiosum virus (MCV).…”

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confidence: 99%

Molluscum Contagiosum Virus Protein MC005 Inhibits NF-κB Activation by Targeting NEMO-Regulated IκB Kinase Activation

Brady

Haas

Farrell

et al. 2017

J Virol

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Molluscum contagiosum virus (MCV), the only known extant humanadapted poxvirus, causes a long-duration infection characterized by skin lesions that typically display an absence of inflammation despite containing high titers of live virus. Despite this curious presentation, MCV is very poorly characterized in terms of host-pathogen interactions. The absence of inflammation around MCV lesions suggests the presence of potent inhibitors of human antiviral immunity and inflammation. However, only a small number of MCV immunomodulatory genes have been characterized in detail. It is likely that many more remain to be discovered, given the density of such sequences in other poxvirus genomes. NF-B activation occurs in response to both virus-induced pattern recognition receptor (PRR) signaling and cellular activation by virus-induced proinflammatory cytokines like tumor necrosis factor and interleukin-1. Activated NF-B drives cytokine and interferon gene expression, leading to inflammation and virus clearance. We report that MC005, which has no orthologs in other poxvirus genomes, is a novel inhibitor of PRR-and cytokinestimulated NF-B activation. MC005 inhibited NF-B proximal to the IB kinase (IKK) complex, and unbiased affinity purification revealed that MC005 interacts with the IKK subunit NEMO (NF-B essential modulator). MC005 binding to NEMO prevents the conformational priming of the IKK complex that occurs when NEMO binds to ubiquitin chains during pathway activation. These data reveal a novel mechanism of poxvirus inhibition of human innate immunity, validate current dynamic models of NEMO-dependent IKK complex activation, and further clarify how the humanadapted poxvirus MCV can so effectively evade antiviral immunity and suppress inflammation to persist in human skin lesions.IMPORTANCE Poxviruses adapt to specific hosts over time, evolving and tailoring elegantly precise inhibitors of the rate-limiting steps within the signaling pathways that control innate immunity and inflammation. These inhibitors reveal new features of the antiviral response, clarify existing models of signaling regulation while offering potent new tools for approaching therapeutic intervention in autoimmunity and inflammatory disease. Molluscum contagiosum virus (MCV) is the only known extant poxvirus specifically adapted to human infection and appears adept at evading normal human antiviral responses, yet it remains poorly characterized. We report the identification of MCV protein MC005 as an inhibitor of the pathways leading to the activation of NF-B, an essential regulator of innate immunity. Further, identification of the mechanism of inhibition of NF-B by MC005 confirms current models of the complex way in which NF-B is regulated and greatly expands our understanding of how MCV so effectively evades human immunity.

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“…Poxviruses inhibit the activation of NF-kB transcription factor; thus, disrupt host signaling pathways that lead to antiviral response [22]. Numerous immunomodulatory proteins are conserved among orthopoxviruses; however certain counterparts of well-known VACV immunomodulatory genes are disrupted in the genome of ECTV [23].…”

Section: Introductionmentioning

confidence: 99%