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[PMID]: 29205134 [Au] Autor: Neuber S; Wagner K; Messerle M; Borst EM [Ad] Endereço: Institute of Virology, Hannover Medical School, Hannover, Germany. [Ti] Título: The C-terminal part of the human cytomegalovirus terminase subunit pUL51 is central for terminase complex assembly. [So] Source: J Gen Virol;99(1):119-134, 2018 Jan. [Is] ISSN: 1465-2099 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The cleavage and packaging of the human cytomegalovirus (HCMV) genome is accomplished by the viral terminase, comprising pUL56 and pUL89, and the recently identified pUL51 subunit. Since knowledge about pUL51 is scarce, we aimed at identifying pUL51 domains that are important for terminase assembly. In silico analysis suggested that the N-terminal half of pUL51 is intrinsically disordered, and that α-helices are present in the C-terminal part. Linker-scanning mutagenesis of pUL51 in the context of the viral genome revealed that amino acid insertions into the predicted α-helices are not compatible with viral growth, whereas upon mutagenesis of the putatively disordered parts interaction with pUL56 and pUL89 was retained and viral progeny was produced. Replacement of pUL51 with the closely related M51 protein of mouse cytomegalovirus did not lead to viable virus, indicating that M51 cannot substitute for pUL51, and swapping the M51 and UL51 N- and C-termini demonstrated the critical role of the pUL51 C-terminal part in building the terminase complex. Notably, the pUL51 C-terminus alone turned out to be sufficient to enable terminase assembly, its nuclear localization and plaque formation. Using HCMV mutants expressing differently tagged pUL51 versions, we did not detect oligomerization of pUL51, as has been proposed for the pUL51 orthologues of other herpesviruses. These data provide an insight into the interaction of pUL51 with the other two terminase components, and provide the basis for unravelling the mode of action of novel antiviral drugs targeting the HCMV terminase. [Mh] Termos MeSH primário: Citomegalovirus/química Endodesoxirribonucleases/química Proteínas Intrinsicamente Desordenadas/química Subunidades Proteicas/química Proteínas Virais/química [Mh] Termos MeSH secundário: Sequência de Aminoácidos Linhagem Celular Citomegalovirus/genética Endodesoxirribonucleases/genética Endodesoxirribonucleases/metabolismo Células Epiteliais Fibroblastos Expressão Gênica Células HeLa Seres Humanos Proteínas Intrinsicamente Desordenadas/genética Proteínas Intrinsicamente Desordenadas/metabolismo Muromegalovirus/química Muromegalovirus/genética Mutação Plasmídeos/química Plasmídeos/metabolismo Conformação Proteica em alfa-Hélice Domínios e Motivos de Interação entre Proteínas Subunidades Proteicas/genética Subunidades Proteicas/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/genética Proteínas Recombinantes/metabolismo Alinhamento de Sequência Transfecção Proteínas Virais/genética Proteínas Virais/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Intrinsically Disordered Proteins); 0 (Protein Subunits); 0 (Recombinant Proteins); 0 (Viral Proteins); EC 3.1.- (Endodeoxyribonucleases); EC 3.1.- (terminase) [Em] Mês de entrada: 1712 [Cu] Atualização por classe: 171229 [Lr] Data última revisão: 171229 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171206 [St] Status: MEDLINE [do] DOI: 10.1099/jgv.0.000984

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[PMID]: 28794018 [Au] Autor: Paust S; Blish CA; Reeves RK [Ad] Endereço: Department of Pediatrics, Center for Human Immunobiology, Texas Children's Hospital, and Department of Pathology and Immunology and Department of Molecular Virology and Microbiology, Digestive Disease Center, Baylor College of Medicine, Houston, Texas, USA silke.paust@bcm.edu rreeves@bidmc.harvard.e [Ti] Título: Redefining Memory: Building the Case for Adaptive NK Cells. [So] Source: J Virol;91(20), 2017 Oct 15. [Is] ISSN: 1098-5514 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Classically, natural killer (NK) cells have been defined by nonspecific innate killing of virus-infected and tumor cells. However, burgeoning evidence suggests that the functional repertoire of NK cells is far more diverse than has been previously appreciated, thus raising the possibility that there may be unexpected functional specialization and even adaptive capabilities among NK cell subpopulations. Some of the first evidence that NK cells respond in an antigen-specific fashion came from experiments revealing that subpopulations of murine NK cells were able to respond to a specific murine cytomegalovirus (MCMV) protein and that in the absence of T and B cells, murine NK cells also mediated adaptive immune responses to a secondary challenge with specific haptens. These data have been followed by demonstrations of NK cell memory of viruses and viral antigens in mice and primates. Herein, we discuss different forms of NK cell antigen specificity and how these responses may be tuned to specific viral pathogens, and we provide assessment of the current literature that may explain molecular mechanisms of the novel phenomenon of NK cell memory. [Mh] Termos MeSH primário: Imunidade Inata Memória Imunológica Células Matadoras Naturais/imunologia [Mh] Termos MeSH secundário: Imunidade Adaptativa Animais Antígenos Virais/imunologia Epitopos Haptenos Seres Humanos Camundongos Muromegalovirus/química Muromegalovirus/imunologia Primatas [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Antigens, Viral); 0 (Epitopes); 0 (Haptens) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171024 [Lr] Data última revisão: 171024 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170811 [St] Status: MEDLINE

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[PMID]: 28760883 [Au] Autor: Nabekura T; Gotthardt D; Niizuma K; Trsan T; Jenus T; Jonjic S; Lanier LL [Ad] Endereço: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143. [Ti] Título: Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient To Drive Expansion during Mouse Cytomegalovirus Infection. [So] Source: J Immunol;199(5):1567-1571, 2017 Sep 01. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: NK cells play a critical role in host defense against viruses. In this study, we investigated the role of NKG2D in the expansion of NK cells after mouse CMV (MCMV) infection. Wild-type and NKG2D-deficient ( ) Ly49H NK cells proliferated robustly when infected with MCMV strains engineered to allow expression of NKG2D ligands, which enhanced the response of wild-type NK cells. Naive NK cells exclusively express NKG2D-L, which pairs only with DAP10, whereas NKG2D-S expressed by activated NK cells pairs with DAP10 and DAP12, similar to Ly49H. However, NKG2D alone was unable to drive robust expansion of Ly49H NK cells when mice were infected with these MCMV strains, likely because NKG2D-S was only transiently expressed postinfection. These findings demonstrate that NKG2D augments Ly49H-dependent proliferation of NK cells; however, NKG2D signaling alone is inadequate for expansion of NK cells, likely due to only transient expression of the NKG2D-DAP12 complex. [Mh] Termos MeSH primário: Infecções por Herpesviridae/imunologia Células Matadoras Naturais/imunologia Muromegalovirus/imunologia Subfamília A de Receptores Semelhantes a Lectina de Células NK/metabolismo Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo [Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transdução de Sinal/genética Proteínas Adaptadoras de Transdução de Sinal/metabolismo Animais Proliferação Celular Células Cultivadas Imunidade Inata Ativação Linfocitária Camundongos Camundongos Endogâmicos C57BL Camundongos Knockout Subfamília A de Receptores Semelhantes a Lectina de Células NK/genética Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética Ligação Proteica Receptores Imunológicos/genética Receptores Imunológicos/metabolismo Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adaptor Proteins, Signal Transducing); 0 (Hcst protein, mouse); 0 (Klra8 protein, mouse); 0 (NK Cell Lectin-Like Receptor Subfamily A); 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (Receptors, Immunologic); 0 (Tyrobp protein, mouse) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170929 [Lr] Data última revisão: 170929 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170802 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1700799

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[PMID]: 28643847 [Au] Autor: Miletic A; Lenartic M; Popovic B; Brizic I; Trsan T; Miklic K; Mandelboim O; Krmpotic A; Jonjic S [Ad] Endereço: Department of Histology and Embryology, Faculty of Medicine, Rijeka, Croatia. [Ti] Título: NCR1-deficiency diminishes the generation of protective murine cytomegalovirus antibodies by limiting follicular helper T-cell maturation. [So] Source: Eur J Immunol;47(9):1443-1456, 2017 Sep. [Is] ISSN: 1521-4141 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: NKp46/NCR1 is an activating NK-cell receptor implicated in the control of various viral and bacterial infections. Recent findings also suggest that it plays a role in shaping the adaptive immune response to pathogens. Using NCR1-deficient (NCR1 ) mice, we provide evidence for the role of NCR1 in antibody response to mouse cytomegalovirus infection (MCMV). The absence of NCR1 resulted in impaired maturation, function and NK-cell migration to regional lymph nodes. In addition, CD4 T-cell activation and follicular helper T-cell (Tfh) generation were reduced, leading to inferior germinal center (GC) B-cell maturation. As a consequence, NCR1 mice produced lower amounts of MCMV-specific antibodies upon infection, which correlated with lower number of virus-specific antibody secreting cells in analyzed lymph nodes. [Mh] Termos MeSH primário: Antígenos Ly/metabolismo Linfócitos B/imunologia Linfócitos T CD4-Positivos/imunologia Centro Germinativo/imunologia Infecções por Herpesviridae/imunologia Células Matadoras Naturais/imunologia Muromegalovirus/imunologia Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo [Mh] Termos MeSH secundário: Animais Anticorpos Antivirais/sangue Antígenos Ly/genética Diferenciação Celular Movimento Celular Células Cultivadas Imunidade Humoral Ativação Linfocitária Camundongos Camundongos Endogâmicos BALB C Camundongos Knockout Receptor 1 Desencadeador da Citotoxicidade Natural/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antibodies, Viral); 0 (Antigens, Ly); 0 (Natural Cytotoxicity Triggering Receptor 1); 0 (Ncr1 protein, mouse) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171010 [Lr] Data última revisão: 171010 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170624 [St] Status: MEDLINE [do] DOI: 10.1002/eji.201646763

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[PMID]: 28542326 [Au] Autor: Chan B; Gonçalves Magalhães V; Lemmermann NAW; Juranic Lisnic V; Stempel M; Bussey KA; Reimer E; Podlech J; Lienenklaus S; Reddehase MJ; Jonjic S; Brinkmann MM [Ad] Endereço: Viral Immune Modulation Research Group, Helmholtz Centre for Infection Research (HZI), Braunschweig, Germany. [Ti] Título: The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription. [So] Source: PLoS Pathog;13(5):e1006382, 2017 May. [Is] ISSN: 1553-7374 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The type I interferon (IFN) response is imperative for the establishment of the early antiviral immune response. Here we report the identification of the first type I IFN antagonist encoded by murine cytomegalovirus (MCMV) that shuts down signaling following pattern recognition receptor (PRR) sensing. Screening of an MCMV open reading frame (ORF) library identified M35 as a novel and strong negative modulator of IFNß promoter induction following activation of both RNA and DNA cytoplasmic PRR. Additionally, M35 inhibits the proinflammatory cytokine response downstream of Toll-like receptors (TLR). Using a series of luciferase-based reporters with specific transcription factor binding sites, we determined that M35 targets NF-κB-, but not IRF-mediated, transcription. Expression of M35 upon retroviral transduction of immortalized bone marrow-derived macrophages (iBMDM) led to reduced IFNß transcription and secretion upon activation of stimulator of IFN genes (STING)-dependent signaling. On the other hand, M35 does not antagonize interferon-stimulated gene (ISG) 56 promoter induction or ISG transcription upon exogenous stimulation of the type I IFN receptor (IFNAR). M35 is present in the viral particle and, upon MCMV infection of fibroblasts, is immediately shuttled to the nucleus where it exerts its immunomodulatory effects. Deletion of M35 from the MCMV genome and hence from the viral particle resulted in elevated type I IFN transcription and secretion in vitro and in vivo. In the absence of M35, lower viral titers are observed during acute infection of the host, and productive infection in the salivary glands was not detected. In conclusion, the M35 protein is released by MCMV immediately upon infection in order to deftly inhibit the antiviral type I IFN response by targeting NF-κB-mediated transcription. The identification of this novel viral protein reinforces the importance of timely countermeasures in the complex relationship between virus and host. [Mh] Termos MeSH primário: Infecções por Citomegalovirus/imunologia Interferon Tipo I/antagonistas & inibidores Muromegalovirus/imunologia Receptores de Reconhecimento de Padrão/metabolismo Transdução de Sinais Proteínas Virais/metabolismo [Mh] Termos MeSH secundário: Animais Infecções por Citomegalovirus/virologia Interferon Tipo I/genética Interferon Tipo I/metabolismo Interferon beta/genética Interferon beta/metabolismo Macrófagos/imunologia Macrófagos/virologia Camundongos Muromegalovirus/genética NF-kappa B/genética NF-kappa B/metabolismo Ligação Proteica Receptores de Reconhecimento de Padrão/genética Receptores Toll-Like/genética Receptores Toll-Like/metabolismo Proteínas Virais/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Interferon Type I); 0 (NF-kappa B); 0 (Receptors, Pattern Recognition); 0 (Toll-Like Receptors); 0 (Viral Proteins); 77238-31-4 (Interferon-beta) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170911 [Lr] Data última revisão: 170911 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170526 [St] Status: MEDLINE [do] DOI: 10.1371/journal.ppat.1006382

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[PMID]: 28432120 [Au] Autor: Pontejo SM; Murphy PM [Ad] Endereço: From the Laboratory of Molecular Immunology, NIAID, National Institutes of Health, Bethesda, Maryland 20892. [Ti] Título: Two glycosaminoglycan-binding domains of the mouse cytomegalovirus-encoded chemokine MCK-2 are critical for oligomerization of the full-length protein. [So] Source: J Biol Chem;292(23):9613-9626, 2017 Jun 09. [Is] ISSN: 1083-351X [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Chemokines are essential for antimicrobial host defenses and tissue repair. Herpesviruses and poxviruses also encode chemokines, copied from their hosts and repurposed for multiple functions, including immune evasion. The CC chemokine MCK-2 encoded by mouse CMV (MCMV) has an atypical structure consisting of a classic chemokine domain N-terminal to a second unique domain, resulting from the splicing of MCMV ORFs and MCK-2 is essential for full MCMV infectivity in macrophages and for persistent infection in the salivary gland. However, information about its mechanism of action and specific biochemical roles for the two domains has been lacking. Here, using genetic, chemical, and enzymatic analyses of multiple mouse cell lines as well as primary mouse fibroblasts from salivary gland and lung, we demonstrate that MCK-2 binds glycosaminoglycans (GAGs) with affinities in the following order: heparin > heparan sulfate > chondroitin sulfate = dermatan sulfate. Both MCK-2 domains bound these GAGs independently, and computational analysis together with site-directed mutagenesis identified five basic residues distributed across the N terminus and the 30s and 50s loops of the chemokine domain that are important GAG binding determinants. Both domains were required for GAG-dependent oligomerization of full-length MCK-2. Thus, MCK-2 is an atypical viral chemokine consisting of a CC chemokine domain and a unique non-chemokine domain, both of which bind GAGs and are critical for GAG-dependent oligomerization of the full-length protein. [Mh] Termos MeSH primário: Quimiocinas CC/química Quimiocinas CC/metabolismo Muromegalovirus/química Muromegalovirus/metabolismo Multimerização Proteica/fisiologia Proteínas Virais/química Proteínas Virais/metabolismo [Mh] Termos MeSH secundário: Animais Quimiocinas CC/genética Glicosaminoglicanos/química Glicosaminoglicanos/genética Glicosaminoglicanos/metabolismo Células HEK293 Seres Humanos Camundongos Muromegalovirus/genética Células NIH 3T3 Fases de Leitura Aberta/fisiologia Domínios Proteicos Estrutura Secundária de Proteína Proteínas Virais/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Chemokines, CC); 0 (Glycosaminoglycans); 0 (MCK-2 protein, Mouse cytomegalovirus 1); 0 (Viral Proteins) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170616 [Lr] Data última revisão: 170616 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170423 [St] Status: MEDLINE [do] DOI: 10.1074/jbc.M117.785121

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[PMID]: 28378389 [Au] Autor: Kavazovic I; Lenartic M; Jelencic V; Jurkovic S; Lemmermann NAW; Jonjic S; Polic B; Wensveen FM [Ad] Endereço: Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia. [Ti] Título: NKG2D stimulation of CD8 T cells during priming promotes their capacity to produce cytokines in response to viral infection in mice. [So] Source: Eur J Immunol;47(7):1123-1135, 2017 Jul. [Is] ISSN: 1521-4141 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: Natural killer group 2 member D (NKG2D) is an activating receptor that is expressed on most cytotoxic cells of the immune system, including NK cells, γδ, and CD8 T cells. It is still a matter of debate whether and how NKG2D mediates priming of CD8 T cells in vivo, due to a lack of studies where NKG2D is eliminated exclusively in these cells. Here, we studied the impact of NKG2D on effector CD8 T-cell formation. NKG2D deficiency that is restricted to murine CD8 T cells did not impair antigen-specific T-cell expansion following mouse CMV and lymphocytic choriomeningitis virus infection, but reduced their capacity to produce cytokines. Upon infection, conventional dendritic cells induce NKG2D ligands, which drive cytokine production on CD8 T cells via the Dap10 signaling pathway. T-cell development, homing, and proliferation were not affected by NKG2D deficiency and cytotoxicity was only impaired when strong T-cell receptor (TCR) stimuli were used. Transfer of antigen-specific CD8 T cells demonstrated that NKG2D deficiency attenuated their capacity to reduce viral loads. The inability of NKG2D-deficient cells to produce cytokines could be overcome with injection of IL-15 superagonist during priming. In summary, our data show that NKG2D has a nonredundant role in priming of CD8 T cells to produce antiviral cytokines. [Mh] Termos MeSH primário: Infecções por Arenaviridae/imunologia Linfócitos T CD8-Positivos/imunologia Citocinas/imunologia Infecções por Herpesviridae/imunologia Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo [Mh] Termos MeSH secundário: Animais Citocinas/biossíntese Citotoxicidade Imunológica Células Dendríticas/imunologia Células Matadoras Naturais/imunologia Ativação Linfocitária Vírus da Coriomeningite Linfocítica/imunologia Camundongos Muromegalovirus Subfamília K de Receptores Semelhantes a Lectina de Células NK/deficiência Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética Receptores Imunológicos/imunologia Receptores Imunológicos/metabolismo Transdução de Sinais [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cytokines); 0 (Hcst protein, mouse); 0 (Klrk1 protein, mouse); 0 (NK Cell Lectin-Like Receptor Subfamily K); 0 (Receptors, Immunologic) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170927 [Lr] Data última revisão: 170927 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170406 [St] Status: MEDLINE [do] DOI: 10.1002/eji.201646805

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[PMID]: 28340350 [Au] Autor: Aguilar OA; Berry R; Rahim MM; Reichel JJ; Popovic B; Tanaka M; Fu Z; Balaji GR; Lau TN; Tu MM; Kirkham CL; Mahmoud AB; Mesci A; Krmpotic A; Allan DS; Makrigiannis AP; Jonjic S; Rossjohn J; Carlyle JR [Ad] Endereço: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada; Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada. [Ti] Título: A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family. [So] Source: Cell;169(1):58-71.e14, 2017 Mar 23. [Is] ISSN: 1097-4172 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a "polar claw" mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay. [Mh] Termos MeSH primário: Células Matadoras Naturais/imunologia Muromegalovirus/imunologia Receptores de Células Matadoras Naturais/imunologia Proteínas Virais/metabolismo [Mh] Termos MeSH secundário: Animais Antígenos Ly/metabolismo Linhagem Celular Células HEK293 Interações Hospedeiro-Patógeno Seres Humanos Evasão da Resposta Imune Imunidade Inata Camundongos Células NIH 3T3 Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo Ratos [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, Ly); 0 (Klrb1b protein, mouse); 0 (Klrb1c protein, mouse); 0 (NK Cell Lectin-Like Receptor Subfamily B); 0 (Receptors, Natural Killer Cell); 0 (Viral Proteins) [Em] Mês de entrada: 1706 [Cu] Atualização por classe: 170614 [Lr] Data última revisão: 170614 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170325 [St] Status: MEDLINE

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[PMID]: 28240600 [Au] Autor: Stacey MA; Clare S; Clement M; Marsden M; Abdul-Karim J; Kane L; Harcourt K; Brandt C; Fielding CA; Smith SE; Wash RS; Brias SG; Stack G; Notley G; Cambridge EL; Isherwood C; Speak AO; Johnson Z; Ferlin W; Jones SA; Kellam P; Humphreys IR [Ti] Título: The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis. [So] Source: J Clin Invest;127(4):1463-1474, 2017 Apr 03. [Is] ISSN: 1558-8238 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: The antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) inhibits cell entry of a number of viruses, and genetic diversity within IFITM3 determines susceptibility to viral disease in humans. Here, we used the murine CMV (MCMV) model of infection to determine that IFITM3 limits herpesvirus-associated pathogenesis without directly preventing virus replication. Instead, IFITM3 promoted antiviral cellular immunity through the restriction of virus-induced lymphopenia, apoptosis-independent NK cell death, and loss of T cells. Viral disease in Ifitm3-/- mice was accompanied by elevated production of cytokines, most notably IL-6. IFITM3 inhibited IL-6 production by myeloid cells in response to replicating and nonreplicating virus as well as following stimulation with the TLR ligands Poly(I:C) and CpG. Although IL-6 promoted virus-specific T cell responses, uncontrolled IL-6 expression in Ifitm3-/- mice triggered the loss of NK cells and subsequently impaired control of MCMV replication. Thus, IFITM3 represents a checkpoint regulator of antiviral immunity that controls cytokine production to restrict viral pathogenesis. These data suggest the utility of cytokine-targeting strategies in the treatment of virus-infected individuals with impaired IFITM3 activity. [Mh] Termos MeSH primário: Citocinas/fisiologia Infecções por Herpesviridae/metabolismo Proteínas de Membrana/fisiologia [Mh] Termos MeSH secundário: Animais Células Cultivadas Infecções por Herpesviridae/imunologia Imunidade Celular Camundongos Camundongos da Linhagem 129 Camundongos Endogâmicos BALB C Camundongos Endogâmicos C57BL Camundongos Knockout Muromegalovirus/fisiologia Receptores de Interleucina-6/metabolismo Transdução de Sinais Internalização do Vírus Replicação Viral [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Cytokines); 0 (Membrane Proteins); 0 (Receptors, Interleukin-6); 0 (fragilis protein, mouse) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170912 [Lr] Data última revisão: 170912 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170228 [St] Status: MEDLINE

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[PMID]: 28202614 [Au] Autor: Erkes DA; Smith CJ; Wilski NA; Caldeira-Dantas S; Mohgbeli T; Snyder CM [Ad] Endereço: Department of Microbiology and Immunology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107. [Ti] Título: Virus-Specific CD8 T Cells Infiltrate Melanoma Lesions and Retain Function Independently of PD-1 Expression. [So] Source: J Immunol;198(7):2979-2988, 2017 Apr 01. [Is] ISSN: 1550-6606 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: It is well known that CD8 tumor-infiltrating lymphocytes (TILs) are correlated with positive prognoses in cancer patients and are used to determine the efficacy of immune therapies. Although it is generally assumed that CD8 TILs will be tumor-associated Ag (TAA) specific, it is unknown whether CD8 T cells with specificity for common pathogens also infiltrate tumors. If so, the presence of these T cells could alter the interpretation of prognostic and diagnostic TIL assays. We compared TAA-specific and virus-specific CD8 T cells in the same tumors using murine CMV, a herpesvirus that causes a persistent/latent infection, and vaccinia virus, a poxvirus that is cleared by the host. Virus-specific CD8 TILs migrated into cutaneous melanoma lesions during acute infection with either virus, after a cleared vaccinia virus infection, and during a persistent/latent murine CMV infection. Virus-specific TILs developed independently of viral Ag in the tumor and, interestingly, expressed low or intermediate levels of full-length PD-1 in the tumor environment. Importantly, PD-1 expression could be markedly induced by Ag but did not correlate with dysfunction for virus-specific TILs, in sharp contrast to TAA-specific TILs in the same tumors. These data suggest that CD8 TILs can reflect an individual's immune status, rather than exclusively representing TAA-specific T cells, and that PD-1 expression on CD8 TILs is not always associated with repeated Ag encounter or dysfunction. Thus, functional virus-specific CD8 TILs could skew the results of prognostic or diagnostic TIL assays. [Mh] Termos MeSH primário: Linfócitos T CD8-Positivos/imunologia Linfócitos do Interstício Tumoral/imunologia Melanoma Experimental/imunologia Viroses/complicações [Mh] Termos MeSH secundário: Transferência Adotiva Animais Antígenos de Neoplasias/imunologia Citometria de Fluxo Infecções por Herpesviridae/complicações Infecções por Herpesviridae/imunologia Melanoma Experimental/complicações Camundongos Camundongos Endogâmicos C57BL Camundongos Transgênicos Muromegalovirus/imunologia Reação em Cadeia da Polimerase Receptor de Morte Celular Programada 1/biossíntese Receptor de Morte Celular Programada 1/imunologia Vaccinia/complicações Vaccinia/imunologia Vírus Vaccinia/imunologia Viroses/imunologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, Neoplasm); 0 (Pdcd1 protein, mouse); 0 (Programmed Cell Death 1 Receptor) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170815 [Lr] Data última revisão: 170815 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170217 [St] Status: MEDLINE [do] DOI: 10.4049/jimmunol.1601064

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