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International Journal of Surgical... Apr 2018
Topics: Antibodies; Biopsy; Condylomata Acuminata; Cross Reactions; Diagnosis, Differential; Humans; Inclusion Bodies, Viral; MART-1 Antigen; Molluscum Contagiosum; Molluscum contagiosum virus; Mucous Membrane; Skin
PubMed: 28805130
DOI: 10.1177/1066896917725805 -
Viruses Aug 2017Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication.... (Review)
Review
Cells have multiple means to induce apoptosis in response to viral infection. Poxviruses must prevent activation of cellular apoptosis to ensure successful replication. These viruses devote a substantial portion of their genome to immune evasion. Many of these immune evasion products expressed during infection antagonize cellular apoptotic pathways. Poxvirus products target multiple points in both the extrinsic and intrinsic apoptotic pathways, thereby mitigating apoptosis during infection. Interestingly, recent evidence indicates that poxviruses also hijack cellular means of eliminating apoptotic bodies as a means to spread cell to cell through a process called apoptotic mimicry. Poxviruses are the causative agent of many human and veterinary diseases. Further, there is substantial interest in developing these viruses as vectors for a variety of uses including vaccine delivery and as oncolytic viruses to treat certain human cancers. Therefore, an understanding of the molecular mechanisms through which poxviruses regulate the cellular apoptotic pathways remains a top research priority. In this review, we consider anti-apoptotic strategies of poxviruses focusing on three relevant poxvirus genera: , , and . All three genera express multiple products to inhibit both extrinsic and intrinsic apoptotic pathways with many of these products required for virulence.
Topics: Animals; Apoptosis; Caspases; Host-Pathogen Interactions; Humans; Immune Evasion; Leporipoxvirus; Molluscipoxvirus; Orthopoxvirus; Poxviridae; Poxviridae Infections; Signal Transduction; Viral Proteins; Virulence; Virus Replication
PubMed: 28786952
DOI: 10.3390/v9080215 -
The Journal of General Virology May 2017Molluscum contagiosum virus (MCV) is the sole member of the Molluscipoxvirus genus and causes a highly prevalent human disease of the skin characterized by the formation...
Molluscum contagiosum virus (MCV) is the sole member of the Molluscipoxvirus genus and causes a highly prevalent human disease of the skin characterized by the formation of a variable number of lesions that can persist for prolonged periods of time. Two major genotypes, subtype 1 and subtype 2, are recognized, although currently only a single complete genomic sequence corresponding to MCV subtype 1 is available. Using next-generation sequencing techniques, we report the complete genomic sequence of four new MCV isolates, including the first one derived from a subtype 2. Comparisons suggest a relatively distant evolutionary split between both MCV subtypes. Further, our data illustrate concurrent circulation of distinct viruses within a population and reveal the existence of recombination events among them. These results help identify a set of MCV genes with potentially relevant roles in molluscum contagiosum epidemiology and pathogenesis.
Topics: Child; Cluster Analysis; Genome, Viral; Healthy Volunteers; High-Throughput Nucleotide Sequencing; Humans; Molluscum contagiosum virus; Phylogeny; Recombination, Genetic; Sequence Analysis, DNA; Sequence Homology
PubMed: 28555548
DOI: 10.1099/jgv.0.000759 -
Journal of Virology Aug 2017Molluscum contagiosum virus (MCV) is a dermatotropic poxvirus that causes benign skin lesions. MCV lesions persist because of virally encoded immune evasion molecules...
Molluscum contagiosum virus (MCV) is a dermatotropic poxvirus that causes benign skin lesions. MCV lesions persist because of virally encoded immune evasion molecules that inhibit antiviral responses. The MCV MC159 protein suppresses NF-κB activation, a powerful antiviral response, via interactions with the NF-κB essential modulator (NEMO) subunit of the IκB kinase (IKK) complex. Binding of MC159 to NEMO does not disrupt the IKK complex, implying that MC159 prevents IKK activation via an as-yet-unidentified strategy. Here, we demonstrated that MC159 inhibited NEMO polyubiquitination, a posttranslational modification required for IKK and downstream NF-κB activation. Because MCV cannot be propagated in cell culture, MC159 was expressed independent of infection or during a surrogate vaccinia virus infection to identify how MC159 prevented polyubiquitination. Cellular inhibitor of apoptosis protein 1 (cIAP1) is a cellular E3 ligase that ubiquitinates NEMO. Mutational analyses revealed that MC159 and cIAP1 each bind to the same NEMO region, suggesting that MC159 may competitively inhibit cIAP1-NEMO interactions. Indeed, MC159 prevented cIAP1-NEMO interactions. MC159 also diminished cIAP1-mediated NEMO polyubiquitination and cIAP1-induced NF-κB activation. These data suggest that MC159 competitively binds to NEMO to prevent cIAP1-induced NEMO polyubiquitination. To our knowledge, this is the first report of a viral protein disrupting NEMO-cIAP1 interactions to strategically suppress IKK activation. All viruses must antagonize antiviral signaling events for survival. We hypothesize that MC159 inhibits NEMO polyubiquitination as a clever strategy to manipulate the host cell environment to the benefit of the virus. Molluscum contagiosum virus (MCV) is a human-specific poxvirus that causes persistent skin neoplasms. The persistence of MCV has been attributed to viral downregulation of host cell immune responses such as NF-κB activation. We show here that the MCV MC159 protein interacts with the NEMO subunit of the IKK complex to prevent NEMO interactions with the cIAP1 E3 ubiquitin ligase. This interaction correlates with a dampening of cIAP1 to polyubiquitinate NEMO and to activate NF-κB. This inhibition of cIAP1-NEMO interactions is a new viral strategy to minimize IKK activation and to control NEMO polyubiquitination. This research provides new insights into mechanisms that persistent viruses may use to cause long-term infection of host cells.
Topics: Animals; Cell Line; Host-Pathogen Interactions; Humans; I-kappa B Kinase; Inhibitor of Apoptosis Proteins; Mice; Molluscum contagiosum virus; Protein Binding; Protein Processing, Post-Translational; Ubiquitination; Viral Proteins
PubMed: 28515292
DOI: 10.1128/JVI.00276-17 -
Journal of Virology Aug 2017Molluscum contagiosum virus (MCV), the only known extant human-adapted poxvirus, causes a long-duration infection characterized by skin lesions that typically display an...
Molluscum contagiosum virus (MCV), the only known extant human-adapted 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-κB 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-κB 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 cytokine-stimulated NF-κB activation. MC005 inhibited NF-κB proximal to the IκB kinase (IKK) complex, and unbiased affinity purification revealed that MC005 interacts with the IKK subunit NEMO (NF-κB 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 human-adapted poxvirus MCV can so effectively evade antiviral immunity and suppress inflammation to persist in human skin lesions. 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-κB, an essential regulator of innate immunity. Further, identification of the mechanism of inhibition of NF-κB by MC005 confirms current models of the complex way in which NF-κB is regulated and greatly expands our understanding of how MCV so effectively evades human immunity.
Topics: Animals; Cell Line; Host-Pathogen Interactions; Humans; I-kappa B Kinase; Immune Evasion; Molluscum contagiosum virus; NF-kappa B; Viral Proteins
PubMed: 28490597
DOI: 10.1128/JVI.00545-17 -
Virus Genes Aug 2017The molluscum contagiosum virus (MCV) uses a variety of immune evasion strategies to antagonize host immune responses. Two MCV proteins, MC159 and MC160, contain tandem...
The molluscum contagiosum virus (MCV) uses a variety of immune evasion strategies to antagonize host immune responses. Two MCV proteins, MC159 and MC160, contain tandem death effector domains (DEDs). They are reported to inhibit innate immune signaling events such as NF-κB and IRF3 activation, and apoptosis. The RxDL motif of MC159 is required for inhibition of both apoptosis and NF-κB activation. However, the role of the conserved RxDL motif in the MC160 DEDs remained unknown. To answer this question, we performed alanine mutations to neutralize the arginine and aspartate residues present in the MC160 RxDL in both DED1 and DED2. These mutations were further modeled against the structure of the MC159 protein. Surprisingly, the RxDL motif was not required for MC160's ability to inhibit MAVS-induced IFNβ activation. Further, unlike previous results with the MC159 protein, mutations within the RxDL motif of MC160 had no effect on the ability of MC160 to dampen TNF-α-induced NF-κB activation. Molecular modeling predictions revealed no overall changes to the structure in the MC160 protein when the amino acids of both RxDL motifs were mutated to alanine (DED1 = R67A D69A; DED2 = R160A D162A). Taken together, our results demonstrate that the RxDL motifs present in the MC160 DEDs are not required for known functions of the viral protein.
Topics: Amino Acid Motifs; Apoptosis; Humans; Immune Evasion; Interferon-beta; Molluscum Contagiosum; Molluscum contagiosum virus; Protein Domains; Tumor Necrosis Factor-alpha; Viral Proteins
PubMed: 28425034
DOI: 10.1007/s11262-017-1456-9 -
Medecine Et Sante Tropicales Feb 2017This article reviews the different types of poxvirus infections. Smallpox, although eradicated, must continue to be monitored because of the potential risk of accidental... (Review)
Review
This article reviews the different types of poxvirus infections. Smallpox, although eradicated, must continue to be monitored because of the potential risk of accidental or voluntary (by bioterrorism) reintroduction. Monkeypox and cowpox viruses are considered to be emergent today ; their high risk of dissemination is due to the increase in international transport as well as trends for new animals as pets and the loss of vaccinal protection against smallpox. Molluscum contagiosum (molluscipoxvirus) causes mild infections, is particularly frequent in children ; in adults it is a marker of the risk of sexually transmitted infections and can, in cases with profuse lesions, reveal AIDS.
Topics: Humans; Mpox (monkeypox); Poxviridae Infections
PubMed: 28406414
DOI: 10.1684/mst.2017.0653 -
Virology May 2017Apoptosis is a powerful host cell defense to prevent viruses from completing replication. Poxviruses have evolved complex means to dampen cellular apoptotic responses....
Apoptosis is a powerful host cell defense to prevent viruses from completing replication. Poxviruses have evolved complex means to dampen cellular apoptotic responses. The poxvirus, Molluscum Contagiosum Virus (MCV), encodes numerous host interacting molecules predicted to antagonize immune responses. However, the function of the majority of these MCV products has not been characterized. Here, we show that the MCV MC163 protein localized to the mitochondria via an N-terminal mitochondrial localization sequence and transmembrane domain. Transient expression of the MC163 protein prevented mitochondrial membrane permeabilization (MMP), an event central to cellular apoptotic responses, induced by either Tumor Necrosis Factor alpha (TNF-α) or carbonyl cyanide 3-chlorophenylhydrazone (CCCP). MC163 expression prevented the release of a mitochondrial intermembrane space reporter protein when cells were challenged with TNF-α. Inhibition of MMP was also observed in cell lines stably expressing MC163. MC163 expression may contribute to the persistence of MCV lesions by dampening cellular apoptotic responses.
Topics: Apoptosis; Caspase 3; Cell Line, Tumor; Cell Membrane Permeability; HeLa Cells; Humans; Hydrazones; Mitochondria; Mitochondrial Membranes; Molluscum Contagiosum; Molluscum contagiosum virus; Poly (ADP-Ribose) Polymerase-1; Staurosporine; Tumor Necrosis Factor-alpha; Viral Proteins
PubMed: 28235685
DOI: 10.1016/j.virol.2017.02.017 -
Lakartidningen Nov 2016Molluscum contagiosum is a viral infection of the epidermis characterized by skin-colored papules or nodules frequently with a central depression. Atypical variants may...
Molluscum contagiosum is a viral infection of the epidermis characterized by skin-colored papules or nodules frequently with a central depression. Atypical variants may occur, primarily in immunosuppressed individuals. We here report a case of »giant Molluscum contagiosum« in an immunocompetent child. The patient was presented with a fairly smooth nodule of 2 cm in diameter on the ring finger. Molluscipoxvirus-like virus particles were detected by electron microscopy from the nodule, but since the clinical picture was not compatible with MC, next generation sequencing was performed in order to verify the diagnosis. Of the total number of obtained sequences, 25% belonged to molluscipoxvirus (MCV) and de novo assembly revealed three contigs corresponding to 95% of the MCV genome. The assembled genome was compared to previously published sequences of the »major envelope protein« used for genotyping of MCV genus. Several unique single nucleotide polymorphisms were identified, which led us to classify this virus as a new subtype of MCV.
Topics: Child, Preschool; Female; Fingers; High-Throughput Nucleotide Sequencing; Humans; Microscopy, Electron; Molluscum Contagiosum; Molluscum contagiosum virus; Sequence Analysis, DNA
PubMed: 27898140
DOI: No ID Found -
JAMA Dermatology Sep 2016
Topics: Age Distribution; Child; Child, Preschool; Female; Humans; Incidence; Male; Molluscum Contagiosum; Molluscum contagiosum virus; Physical Examination; Remission, Spontaneous; Severity of Illness Index
PubMed: 27627044
DOI: 10.1001/jamadermatol.2016.2367