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1.
PLoS Pathog ; 15(4): e1007711, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31034515

RESUMO

The human specific poxvirus molluscum contagiosum virus (MCV) produces skin lesions that can persist with minimal inflammation, suggesting that the virus has developed robust immune evasion strategies. However, investigations into the underlying mechanisms of MCV pathogenesis have been hindered by the lack of a model system to propagate the virus. Herein we demonstrate that MCV-encoded MC80 can disrupt MHC-I antigen presentation in human and mouse cells. MC80 shares moderate sequence-similarity with MHC-I and we find that it associates with components of the peptide-loading complex. Expression of MC80 results in ER-retention of host MHC-I and thereby reduced cell surface presentation. MC80 accomplishes this by engaging tapasin via its luminal domain, targeting it for ubiquitination and ER-associated degradation in a process dependent on the MC80 transmembrane region and cytoplasmic tail. Tapasin degradation is accompanied by a loss of TAP, which limits MHC-I access to cytosolic peptides. Our findings reveal a unique mechanism by which MCV undermines adaptive immune surveillance.


Assuntos
Apresentação do Antígeno/imunologia , Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Proteínas de Membrana Transportadoras/metabolismo , Molusco Contagioso/imunologia , Vírus do Molusco Contagioso/imunologia , Proteínas Virais/metabolismo , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Células Cultivadas , Humanos , Evasão da Resposta Imune , Camundongos , Molusco Contagioso/metabolismo , Molusco Contagioso/virologia , Linfócitos T Citotóxicos/imunologia , Proteínas Virais/genética
2.
Viruses ; 10(11)2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30373153

RESUMO

Molluscum contagiosum virus (MCV) is the sole member of the Molluscipoxvirus genus and the causative agent of molluscum contagiosum (MC), a common skin disease. Although it is an important and frequent human pathogen, its genetic landscape and evolutionary history remain largely unknown. In this study, ten novel complete MCV genome sequences of the two most common MCV genotypes were determined (five MCV1 and five MCV2 sequences) and analyzed together with all MCV complete genomes previously deposited in freely accessible sequence repositories (four MCV1 and a single MCV2). In comparison to MCV1, a higher degree of nucleotide sequence conservation was observed among MCV2 genomes. Large-scale recombination events were identified in two newly assembled MCV1 genomes and one MCV2 genome. One recombination event was located in a newly identified recombinant region of the viral genome, and all previously described recombinant regions were re-identified in at least one novel MCV genome. MCV genes comprising the identified recombinant segments have been previously associated with viral interference with host T-cell and NK-cell immune responses. In conclusion, the two most common MCV genotypes emerged along divergent evolutionary pathways from a common ancestor, and the differences in the heterogeneity of MCV1 and MCV2 populations may be attributed to the strictness of the constraints imposed by the host immune response.


Assuntos
Genoma Viral , Genômica , Molusco Contagioso/virologia , Vírus do Molusco Contagioso/genética , Quimiotaxia/imunologia , Biologia Computacional/métodos , Evolução Molecular , Variação Genética , Genômica/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunidade , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Anotação de Sequência Molecular , Molusco Contagioso/imunologia , Vírus do Molusco Contagioso/imunologia , Mosaicismo , Filogenia , Recombinação Genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Carga Viral
3.
J Gen Virol ; 99(2): 246-252, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29393023

RESUMO

Molluscum contagiosum virus (MCV) causes persistent, benign skin neoplasm in children and adults. MCV is refractive to growth in standard tissue culture and there is no relevant animal model of infection. Here we investigated whether another poxvirus (vaccinia virus; VACV) could be used to examine MCV immunoevasion protein properties in vivo. The MCV MC159L or MC160L genes, which encode NF-κB antagonists, were inserted into an attenuated VACV lacking an NF-κB antagonist (vΔA49), creating vMC159 and vMC160. vMC160 slightly increased vΔA49 virulence in the intranasal and intradermal routes of inoculation. vMC159 infection was less virulent than vΔA49 in both inoculation routes. vMC159-infected ear pinnae did not form lesions, but virus replication still occurred. Thus, the lack of lesions was not due to abortive virus replication. This system provides a new approach to examine MCV immunoevasion proteins within the context of a complete and complex immune system.


Assuntos
Vírus do Molusco Contagioso/imunologia , NF-kappa B/antagonistas & inibidores , Vírus Vaccinia/patogenicidade , Proteínas Virais/administração & dosagem , Administração Intranasal , Animais , Criança , Feminino , Humanos , Injeções Intradérmicas , Camundongos Endogâmicos BALB C , Vírus do Molusco Contagioso/genética , Proteínas Virais/imunologia , Virulência
6.
Curr Protoc Microbiol ; 47: 14A.6.1-14A.6.9, 2017 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-29120484

RESUMO

Molluscum contagiosum virus (MCV) is a common skin pathogen of children and young adults. Infection with MCV causes benign skin tumors in children and young adults and is mostly self-limiting. In contrast to orthopoxviruses, MCV infections tend to take a subacute clinical course but may persist for up to 12 months. Current numbers for MCV seroprevalence in different geographical areas are based on a variety of historical serological methods from complement fixation assays to MCV ELISAs based on purified MCV virions and MC133 antigen expressed in a Semliki Forest Virus expression system. A standardized ELISA for the assessment of MCV seroprevalence would be useful to determine global MCV seroprevalence. The methods described show that polypeptides derived from MCV open reading frames MC084 (residues V123 to R230 and V33 to G117), mc133 (residues M1 to N370), and glutathione S-transferase (GST)-H3L (residues I142 to W251) expressed in E. coli RIL+ as GST fusion proteins can be used to assess antibody binding in a GST capture ELISA. We show how the ELISA can be used to screen a panel of patient sera previously characterized with the mc084 V123-R230 ELISA. © 2017 by John Wiley & Sons, Inc.


Assuntos
Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Molusco Contagioso/diagnóstico por imagem , Vírus do Molusco Contagioso/imunologia , Antígenos Virais/genética , Antígenos Virais/imunologia , Humanos , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Estudos Soroepidemiológicos
7.
Virus Genes ; 53(4): 522-531, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28425034

RESUMO

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 IFNß 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.


Assuntos
Evasão da Resposta Imune , Molusco Contagioso/virologia , Vírus do Molusco Contagioso/imunologia , Proteínas Virais/química , Proteínas Virais/imunologia , Motivos de Aminoácidos , Apoptose , Humanos , Interferon beta/genética , Interferon beta/imunologia , Molusco Contagioso/genética , Molusco Contagioso/imunologia , Molusco Contagioso/fisiopatologia , Vírus do Molusco Contagioso/química , Vírus do Molusco Contagioso/genética , Domínios Proteicos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Proteínas Virais/genética
8.
Dermatol Online J ; 22(1)2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26990479

RESUMO

A three-year-old boy presented to our oculoplastic clinic with complaints of painless gradually increasing right upper lid mass for the last 6 months. On examination a firm mass measuring roughly 1x1 cm was present on the upper lid. The mass was non tender with fine superficial vessels running over it. A differential diagnosis of epidermoid cyst, vascular malformation, pilomatrixoma, and juvenile xanthogranuloma was considered. The patient underwent excisional biopsy of the mass. On gross examination the mass had a brain like appearance. Histopathological examination confirmed the diagnosis of molluscum contagiosum. It is rare for molluscum contagiosum to present as a solitary lid tumor. A brain like appearance of the excised mass can provide a clue towards the diagnosis.


Assuntos
Neoplasias Palpebrais/diagnóstico , Pálpebras/patologia , Hospedeiro Imunocomprometido , Molusco Contagioso/diagnóstico , Dermatopatias Virais/diagnóstico , Anticorpos Antivirais/análise , Pré-Escolar , Procedimentos Cirúrgicos Dermatológicos/métodos , Diagnóstico Diferencial , Pálpebras/cirurgia , Pálpebras/virologia , Humanos , Masculino , Molusco Contagioso/cirurgia , Vírus do Molusco Contagioso/imunologia , Dermatopatias Virais/cirurgia
9.
Mult Scler ; 22(7): 969-71, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26860987

RESUMO

Fingolimod-related viral infections have been described on several occasions since its introduction in 2010. We hereby add a report on an otherwise immunocompetent, 18-year old Caucasian man with relapsing-remitting multiple sclerosis who developed a protracted and extensive molluscum contagiosum (MC) virus infection shortly after being started on fingolimod. Wide-spread cutaneous MC infections in adult patients are considered indicative of underlying immunosuppression. Neurologists prescribing fingolimod ought to be aware of a possibly increased risk of MC, but also need to know about its relative benignity, lack of extra-cutaneous complications, and adequate treatment options.


Assuntos
Cloridrato de Fingolimode/efeitos adversos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Molusco Contagioso/induzido quimicamente , Vírus do Molusco Contagioso/imunologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Infecções Oportunistas/induzido quimicamente , Adolescente , Biópsia , Humanos , Masculino , Molusco Contagioso/diagnóstico , Molusco Contagioso/imunologia , Molusco Contagioso/virologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/imunologia , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/imunologia , Infecções Oportunistas/virologia , Fatores de Risco
10.
J Virol ; 89(16): 8406-15, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26041281

RESUMO

Molluscum contagiosum virus (MCV) is unique in being the only known extant, human-adapted poxvirus, yet to date, it is very poorly characterized in terms of host-pathogen interactions. MCV causes persistent skin lesions filled with live virus, but these are generally immunologically silent, suggesting the presence of potent inhibitors of human antiviral immunity and inflammation. Fewer than five MCV immunomodulatory genes have been characterized in detail, but it is likely that many more remain to be discovered given the density of such sequences in all well-characterized poxviruses. Following virus infection, NF-B activation occurs in response to both pattern recognition receptor (PRR) signaling and cellular activation by virus-elicited proinflammatory cytokines, such as tumor necrosis factor (TNF). As such, NF-B activation is required for virus detection, antiviral signaling, inflammation, and clearance of viral infection. Hence, we screened a library of MCV genes for effects on TNF-stimulated NF-B activation. This revealed MC132, a unique protein with no orthologs in other poxviral genomes, as a novel inhibitor of NF-B. Interestingly, MC132 also inhibited PRR- and virus-activated NF-B, since MC132 interacted with the NF-B subunit p65 and caused p65 degradation. Unbiased affinity purification to identify host targets of MC132 revealed that MC132 acted by targeting NF-B p65 for ubiquitin-dependent proteasomal degradation by recruiting p65 to a host Cullin-5/Elongin B/Elongin C complex. These data reveal a novel mechanism for poxviral inhibition of human innate immunity and further clarify how the human-adapted poxvirus MCV can so effectively evade antiviral immunity to persist in skin lesions.


Assuntos
Tolerância Imunológica/imunologia , Imunidade Inata/imunologia , Vírus do Molusco Contagioso/imunologia , NF-kappa B/metabolismo , Proteínas Virais/imunologia , eIF-2 Quinase/metabolismo , Cromatografia Líquida , Ensaio de Imunoadsorção Enzimática , Humanos , Immunoblotting , Imunoprecipitação , Microscopia Confocal , Vírus do Molusco Contagioso/metabolismo , Oligonucleotídeos/genética , Proteólise , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Reconhecimento de Padrão/metabolismo , Espectrometria de Massas em Tandem , Proteínas Virais/metabolismo
11.
Adv Virus Res ; 92: 201-52, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25701888

RESUMO

Molluscum contagiosum virus (MCV) is the causative agent of molluscum contagiosum (MC), the third most common viral skin infection in children, and one of the five most prevalent skin diseases worldwide. No FDA-approved treatments, vaccines, or commercially available rapid diagnostics for MCV are available. This review discusses several aspects of this medically important virus including: physical properties of MCV, MCV pathogenesis, MCV replication, and immune responses to MCV infection. Sequencing of the MCV genome revealed novel immune evasion molecules which are highlighted here. Special attention is given to the MCV MC159 and MC160 proteins. These proteins are FLIPs with homologs in gamma herpesviruses and in the cell. They are of great interest because each protein regulates apoptosis, NF-κB, and IRF3. However, the mechanism that each protein uses to impart its effects is different. It is important to elucidate how MCV inhibits immune responses; this knowledge contributes to our understanding of viral pathogenesis and also provides new insights into how the immune system neutralizes virus infections.


Assuntos
Evasão da Resposta Imune , Molusco Contagioso/imunologia , Vírus do Molusco Contagioso/imunologia , Animais , Interações Hospedeiro-Patógeno , Humanos , Molusco Contagioso/virologia , Vírus do Molusco Contagioso/genética , Proteínas Virais/genética , Proteínas Virais/imunologia
12.
J Virol ; 90(6): 2895-905, 2015 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-26719271

RESUMO

UNLABELLED: Molluscum contagiosum virus (MCV) gene MC159 encodes a viral FLICE inhibitory protein (vFLIP) that inhibits caspase-8-mediated apoptosis. The MC159 protein was also reported to inhibit programmed necrosis (necroptosis) and modulate NF-κB activation by interacting with RIP1 and NEMO. The importance of MC159 during MCV infection has remained unknown, as there is no system for propagation and genetic manipulation of this virus. Here we investigated the functions of MC159 during viral infection using murine cytomegalovirus (MCMV) as a surrogate virus. MC159 was inserted into the MCMV genome, replacing M36 or M45, two MCMV genes with functions similar to those reported for MC159. M36 encodes a viral inhibitor of caspase-8-induced apoptosis (vICA) and M45 a viral inhibitor of RIP activation (vIRA), which inhibits RIP1/RIP3-mediated necroptosis. The M45 protein also blocks NF-κB activation by interacting with NEMO. When expressed by MCMV, MC159 blocked tumor necrosis factor alpha (TNF-α)-induced apoptosis of infected cells and partially restored MCMV replication in macrophages. However, MC159 did not fully replace M45, as it did not inhibit necroptosis in murine cells, but it reduced TNF-α-induced necroptosis in MCMV-infected human HT-29 cells. MC159 also differed from M45 in its effect on NF-κB. While MCMV-encoded M45 blocked NF-κB activation by TNF-α and interleukin-1ß (IL-1ß), MC159 inhibited TNF-α- but not IL-1ß-induced NF-κB activation in infected mouse fibroblasts. These results indicate that the spectrum of MC159's functions differs depending on cell type and expression system and that a cell culture system for the propagation of MCV is needed to determine the biological relevance of presumed viral gene functions. IMPORTANCE: MCV is a human-pathogenic poxvirus that cannot be propagated in cell culture or laboratory animals. Therefore, MCV gene products have been studied predominantly in cells expressing individual viral genes. In this study, we analyzed the function of the MCV gene MC159 by expressing it from a different virus and comparing its functions to those of two well-characterized MCMV genes. In this system, MC159 displayed some but not all of the previously described functions, suggesting that the functions of a viral gene depend on the conditions under which it is expressed. Until a cell culture system for the analysis of MCV becomes available, it might be necessary to analyze MCV genes in several different systems to extrapolate their biological importance.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Fatores Imunológicos/metabolismo , Vírus do Molusco Contagioso/fisiologia , Muromegalovirus/fisiologia , Proteínas Virais/metabolismo , Animais , Linhagem Celular , Sobrevivência Celular , Humanos , Camundongos , Vírus do Molusco Contagioso/genética , Vírus do Molusco Contagioso/imunologia , Muromegalovirus/genética , Muromegalovirus/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Virais/genética
13.
PLoS One ; 9(2): e88734, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24558417

RESUMO

Molluscum contagiosum virus (MCV) is a significant but underreported skin pathogen for children and adults. Seroprevalence studies can help establish burden of disease. Enzyme linked immunosorbent assay (ELISA) based studies have been published for Australian and Japanese populations and the results indicate seroprevalences between 6 and 22 percent in healthy individuals, respectively. To investigate seroprevalence in Europe, we have developed a recombinant ELISA using a truncated MCV virion surface protein MC084 (V123-R230) expressed in E. coli. The ELISA was found to be sensitive and specific, with low inter- and intra-assay variability. Sera from 289 German adults and children aged 0-40 years (median age 21 years) were analysed for antibodies against MC084 by direct binding ELISA. The overall seropositivity rate was found to be 14.8%. The seropositivity rate was low in children below the age of one (4.5%), peaked in children aged 2-10 years (25%), and fell again in older populations (11-40 years; 12.5%). Ten out of 33 healthy UK individuals (30.3%; median age 27 years) had detectable MC084 antibodies. MCV seroconversion was more common in dermatological and autoimmune disorders, than in immunocompromised patients or in patients with multiple sclerosis. Overall MCV seroprevalence is 2.1 fold higher in females than in males in a UK serum collection. German seroprevalences determined in the MC084 ELISA (14.8%) are at least three times higher than incidence of MC in a comparable Swiss population (4.9%). While results are not strictly comparable, this is lower than Australian seroprevalence in a virion based ELISA (n = 357; 23%; 1999), but higher than the seroprevalence reported in a Japanese study using an N-terminal truncation of MC133 (n = 108, 6%; 2000. We report the first large scale serological survey of MC in Europe (n = 393) and the first MCV ELISA based on viral antigen expressed in E. coli.


Assuntos
Ensaio de Imunoadsorção Enzimática/métodos , Vírus do Molusco Contagioso/isolamento & purificação , Adolescente , Adulto , Antígenos Virais/imunologia , Criança , Pré-Escolar , Clonagem Molecular , Escherichia coli/genética , Feminino , Alemanha , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Vírus do Molusco Contagioso/imunologia , Estudos Soroepidemiológicos , Solubilidade , Reino Unido , Proteínas Virais/química , Proteínas Virais/genética , Proteínas Virais/imunologia , Adulto Jovem
14.
Proc Natl Acad Sci U S A ; 111(2): E265-72, 2014 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-24379396

RESUMO

Apoptosis, NF-κB activation, and IRF3 activation are a triad of intrinsic immune responses that play crucial roles in the pathogenesis of infectious diseases, cancer, and autoimmunity. FLIPs are a family of viral and cellular proteins initially found to inhibit apoptosis and more recently to either up- or down-regulate NF-κB. As such, a broad role for FLIPs in disease regulation is postulated, but exactly how a FLIP performs such multifunctional roles remains to be established. Here we examine FLIPs (MC159 and MC160) encoded by the molluscum contagiosum virus, a dermatotropic poxvirus causing skin infections common in children and immunocompromised individuals, to better understand their roles in viral pathogenesis. While studying their molecular mechanisms responsible for NF-κB inhibition, we discovered that each protein inhibited IRF3-controlled luciferase activity, identifying a unique function for FLIPs. MC159 and MC160 each inhibited TBK1 phosphorylation, confirming this unique function. Surprisingly, MC159 coimmunoprecipitated with TBK1 and IKKε but MC160 did not, suggesting that these homologs use distinct molecular mechanisms to inhibit IRF3 activation. Equally surprising was the finding that the FLIP regions necessary for TBK1 inhibition were distinct from those MC159 or MC160 regions previously defined to inhibit NF-κB or apoptosis. These data reveal previously unappreciated complexities of FLIPs, and that subtle differences within the conserved regions of FLIPs possess distinct molecular and structural fingerprints that define crucial differences in biological activities. A future comparison of mechanistic differences between viral FLIP proteins can provide new means of precisely manipulating distinct aspects of intrinsic immune responses.


Assuntos
Interferon beta/antagonistas & inibidores , Molusco Contagioso/imunologia , Vírus do Molusco Contagioso/genética , Proteínas Virais/metabolismo , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Quinase I-kappa B/metabolismo , Immunoblotting , Imunoprecipitação , Luciferases/antagonistas & inibidores , Vírus do Molusco Contagioso/imunologia , NF-kappa B/antagonistas & inibidores , Fosforilação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Virais/farmacologia
15.
Lancet Infect Dis ; 13(10): 877-88, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23972567

RESUMO

Molluscum contagiosum virus is an important human skin pathogen: it can cause disfigurement and suffering in children, in adults it is less common and often sexually transmitted. Extensive and persistent skin infection with the virus can indicate underlying immunodeficiency. Traditional ablative therapies have not been compared directly with newer immune-modulating and specific antiviral therapies. Advances in research raise the prospect of new approaches to treatment informed by the biology of the virus; in human skin, the infection is localised in the epidermal layers, where it induces a typical, complex hyperproliferative lesion with an abundance of virus particles but a conspicuous absence of immune effectors. Functional studies of the viral genome have revealed effects on cellular pathways involved in the cell cycle, innate immunity, inflammation, and cell death. Extensive lesions caused by molluscum contagiosum can occur in patients with DOCK8 deficiency-a genetic disorder affecting migration of dendritic and specialised T cells in skin. Sudden disappearance of lesions is the consequence of a vigorous immune response in healthy people. Further study of the unique features of infection with molluscum contagiosum virus could give fundamental insight into the nature of skin immunity.


Assuntos
Molusco Contagioso/virologia , Vírus do Molusco Contagioso , Humanos , Molusco Contagioso/imunologia , Molusco Contagioso/patologia , Vírus do Molusco Contagioso/imunologia
17.
J Immunol ; 188(5): 2371-9, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22301546

RESUMO

Molluscum contagiosum virus (MCV) causes persistent neoplasms in healthy and immunocompromised people. Its ability to persist likely is due to its arsenal of viral immunoevasion proteins. For example, the MCV MC159 protein inhibits TNF-R1-induced NF-κB activation and apoptosis. The MC159 protein is a viral FLIP and, as such, possesses two tandem death effector domains (DEDs). We show in this article that, in human embryonic kidney 293 T cells, the expression of wild-type MC159 or a mutant MC159 protein containing the first DED (MC159 A) inhibited TNF-induced NF-κB, or NF-κB activated by PMA or MyD88 overexpression, whereas a mutant protein lacking the first DED (MC159 B) did not. We hypothesized that the MC159 protein targeted the IκB kinase (IKK) complex to inhibit these diverse signaling events. Indeed, the MC159 protein, but not MC159 B, coimmunoprecipitated with IKKγ. MC159 coimmunoprecipitated with IKKγ when using mouse embryonic fibroblasts that lack either IKKα or IKKß, suggesting that the MC159 protein interacted directly with IKKγ. MC159-IKKγ coimmunoprecipitations were detected during infection of cells with either MCV isolated from human lesions or with a recombinant MC159-expressing vaccinia virus. MC159 also interacts with TRAF2, a signaling molecule involved in NF-κB activation. However, mutational analysis of MC159 failed to reveal a correlation between MC159-TRAF2 interactions and MC159's inhibitory function. We propose that MC159-IKK interactions, but not MC159-TRAF2 interactions, are responsible for inhibiting NF-κB activation.


Assuntos
Quinase I-kappa B/metabolismo , Vírus do Molusco Contagioso/imunologia , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Proteínas Virais/fisiologia , Animais , Comunicação Celular/imunologia , Células HEK293 , Humanos , Quinase I-kappa B/fisiologia , Camundongos , Molusco Contagioso/enzimologia , Molusco Contagioso/imunologia , Molusco Contagioso/metabolismo , NF-kappa B/fisiologia
18.
Virology ; 417(2): 449-56, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21802105

RESUMO

Molluscum contagiosum poxvirus (MCV) type 1 and type 2 encode two chemokine-like proteins MC148R1 and MC148R2. It is believed that MC148R proteins function by blocking the inflammatory response. However, the mechanism of the proposed biological activities of MC148R proteins and the role of the additional C-terminal cysteines that do not exist in other chemokines are not understood. Here, we demonstrated in two different assay systems that His-tagged MC148R1 displaces the interaction between CXCL12α and CXCR4. The N-terminal cysteines but not the additional C-terminal cysteines modulate this displacement. His-tagged MC148R1 blocked both CXCL12α-mediated and MIP-1α-mediated chemotaxis. In contrast, MC148R2 blocked MIP-1α-mediated but not CXCL12α-mediated chemotaxis. Immunoprecipitation by antibodies to MC148R1 or CXCL12α followed by immunoblotting and detection by antibodies to the other protein demonstrated physical interaction of His-tagged CXCL12α and His-tagged MC148R1. Interaction with chemokines might mask the receptor interaction site resulting in decreased binding and impairment of the biological activities.


Assuntos
Quimiocina CXCL12/antagonistas & inibidores , Quimiocinas CC/imunologia , Quimiocinas CC/metabolismo , Cisteína/metabolismo , Interações Hospedeiro-Patógeno , Vírus do Molusco Contagioso/patogenicidade , Receptores CXCR4/antagonistas & inibidores , Proteínas Virais/imunologia , Proteínas Virais/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular , Quimiocinas CC/genética , Quimiotaxia , Cisteína/genética , Humanos , Immunoblotting , Imunoprecipitação , Camundongos , Dados de Sequência Molecular , Vírus do Molusco Contagioso/imunologia , Ligação Proteica , Mapeamento de Interação de Proteínas , Alinhamento de Sequência , Proteínas Virais/genética
19.
J Virol ; 84(20): 10467-76, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20702623

RESUMO

Viral inhibitors of host programmed cell death (PCD) are widely believed to promote viral replication by preventing or delaying host cell death. Viral FLIPs (Fas-linked ICE-like protease [FLICE; caspase-8]-like inhibitor proteins) are potent inhibitors of death receptor-induced apoptosis and programmed necrosis. Surprisingly, transgenic expression of the viral FLIP MC159 from molluscum contagiosum virus (MCV) in mice enhanced rather than inhibited the innate immune control of vaccinia virus (VV) replication. This effect of MC159 was specifically manifested in peripheral tissues such as the visceral fat pad, but not in the spleen. VV-infected MC159 transgenic mice mounted an enhanced innate inflammatory reaction characterized by increased expression of the chemokine CCL-2/MCP-1 and infiltration of γδ T cells into peripheral tissues. Radiation chimeras revealed that MC159 expression in the parenchyma, but not in the hematopoietic compartment, is responsible for the enhanced innate inflammatory responses. The increased inflammation in peripheral tissues was not due to resistance of lymphocytes to cell death. Rather, we found that MC159 facilitated Toll-like receptor 4 (TLR4)- and tumor necrosis factor (TNF)-induced NF-κB activation. The increased NF-κB responses were mediated in part through increased binding of RIP1 to TNFRSF1A-associated via death domain (TRADD), two crucial signal adaptors for NF-κB activation. These results show that MC159 is a dual-function immune modulator that regulates host cell death as well as NF-κB responses by innate immune signaling receptors.


Assuntos
Vaccinia/imunologia , Proteínas Virais/imunologia , Animais , Apoptose/imunologia , Sequência de Bases , Primers do DNA/genética , Proteínas Ativadoras de GTPase/metabolismo , Expressão Gênica , Genes Virais , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Lipopolissacarídeos/toxicidade , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/lesões , Fígado/patologia , Camundongos , Camundongos Transgênicos , Vírus do Molusco Contagioso/genética , Vírus do Molusco Contagioso/imunologia , NF-kappa B/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Receptor 4 Toll-Like/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Vaccinia/patologia , Vaccinia/virologia , Vírus Vaccinia/imunologia , Vírus Vaccinia/patogenicidade , Vírus Vaccinia/fisiologia , Proteínas Virais/genética , Replicação Viral/imunologia
20.
Acta pediatr. esp ; 68(2): 91-94, feb. 2010. ilus
Artigo em Espanhol | IBECS | ID: ibc-85921

RESUMO

El molusco contagioso es una enfermedad vírica común en la infancia, que se presenta como pápulas umbilicadas firmes y pequeñas. Dado que se considera una enfermedad autolimitada, hay un debate continuo sobre si las lesiones asociadas se deben tratar o esperar a que se resuelvan espontáneamente. Sin embargo, las lesiones tardan entre 6 y 48 meses en curarse, y generan una gran preocupación tanto en los niños (a menudo limitan su asistencia al colegio y su actividad social) como en los cuidadores. El tratamiento puede acortar el curso de la enfermedad, posiblemente reduce la autoinoculación y la transmisión, e incrementa la calidad de vida del paciente (AU)


Molluscum contagiosum is a common viral disease of childhood which presents itself as small, firm, umbilicated papules. Since it is considered a self-limiting disease, debate continues about whether lesions associated with this disease should be treated or allowed to resolve spontaneously. However, the lesions take between 6 and 48 months to resolve and are a source of great embarrassment for both carers and children, often affecting the children’s attendance at school and limiting their social activity. Treatment can shorten the disease course, possibly reducing autoinoculation and transmission, and increases the patients’ quality of life (AU)


Assuntos
Humanos , Masculino , Feminino , Criança , Molusco Contagioso/complicações , Molusco Contagioso/diagnóstico , Molusco Contagioso/terapia , Qualidade de Vida , Vírus do Molusco Contagioso , Vírus do Molusco Contagioso/imunologia , Vírus do Molusco Contagioso/patogenicidade
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