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1.
Nat Immunol ; 19(9): 973-985, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30127434

RESUMO

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.


Assuntos
Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Células Dendríticas/imunologia , Proteínas de Membrana/metabolismo , Infecções por Mycobacterium/imunologia , Mycobacterium bovis/fisiologia , Mycobacterium tuberculosis/fisiologia , Células Th1/imunologia , Tuberculose/imunologia , Animais , Antígenos de Diferenciação de Linfócitos B/metabolismo , Células Cultivadas , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunidade , Memória Imunológica , Lactente , Interferon gama/metabolismo , Linfadenopatia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/genética , Infecções por Mycobacterium/genética , Vacinação
2.
Nature ; 518(7540): 547-51, 2015 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-25470051

RESUMO

Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2(+) (also known as Tek) cellular pathway generating Csf1r(+) erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.


Assuntos
Linhagem da Célula , Eritrócitos/citologia , Hematopoese , Macrófagos/citologia , Células-Tronco/citologia , Saco Vitelino/citologia , Animais , Proliferação de Células , Rastreamento de Células , Feminino , Feto/citologia , Granulócitos/citologia , Células de Kupffer/citologia , Células de Langerhans/citologia , Fígado/citologia , Fígado/embriologia , Macrófagos Alveolares/citologia , Masculino , Camundongos , Microglia/citologia , Monócitos/citologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptor TIE-2/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo
3.
Immunity ; 33(3): 375-86, 2010 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-20832340

RESUMO

Monocytes are effectors of the inflammatory response to microbes. Human CD14(+) monocytes specialize in phagocytosis and production of reactive oxygen species and secrete inflammatory cytokines in response to a broad range of microbial cues. Here, we have characterized the functions of human monocytes that lack CD14 (CD14(dim)) and express CD16. CD14(dim) monocytes were genetically distinct from natural killer cells. Gene expression analyses indicated similarities with murine patrolling Gr1(dim) monocytes, and they patrolled the endothelium of blood vessels after adoptive transfer, in a lymphocyte function-associated antigen-1-dependent manner. CD14(dim) monocytes were weak phagocytes and did not produce ROS or cytokines in response to cell-surface Toll-like receptors. Instead, they selectively produced TNF-α, IL-1ß, and CCL3 in response to viruses and immune complexes containing nucleic acids, via a proinflammatory TLR7-TLR 8-MyD88-MEK pathway. Thus, CD14(dim) cells are bona fide monocytes involved in the innate local surveillance of tissues and the pathogenesis of autoimmune diseases.


Assuntos
Receptores de Lipopolissacarídeos/fisiologia , Monócitos/fisiologia , Ácidos Nucleicos/fisiologia , Receptor 7 Toll-Like/fisiologia , Receptor 8 Toll-Like/fisiologia , Vírus/imunologia , Animais , Apresentação de Antígeno , Citocinas/biossíntese , Proteínas Ligadas por GPI , Antígenos HLA-DR/análise , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Fator 88 de Diferenciação Mieloide/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de IgG/análise
4.
N Engl J Med ; 365(2): 127-38, 2011 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-21524210

RESUMO

BACKGROUND: The genetic analysis of human primary immunodeficiencies has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. Disseminated infection caused by bacille Calmette-Guérin (BCG) vaccines is an early manifestation of primary immunodeficiencies, such as severe combined immunodeficiency. In many affected persons, the cause of disseminated BCG disease is unexplained. METHODS: We evaluated an infant presenting with features of severe immunodeficiency, including early-onset disseminated BCG disease, who required hematopoietic stem-cell transplantation. We also studied two otherwise healthy subjects with a history of disseminated but curable BCG disease in childhood. We characterized the monocyte and dendritic-cell compartments in these three subjects and sequenced candidate genes in which mutations could plausibly confer susceptibility to BCG disease. RESULTS: We detected two distinct disease-causing mutations affecting interferon regulatory factor 8 (IRF8). Both K108E and T80A mutations impair IRF8 transcriptional activity by disrupting the interaction between IRF8 and DNA. The K108E variant was associated with an autosomal recessive severe immunodeficiency with a complete lack of circulating monocytes and dendritic cells. The T80A variant was associated with an autosomal dominant, milder immunodeficiency and a selective depletion of CD11c+CD1c+ circulating dendritic cells. CONCLUSIONS: These findings define a class of human primary immunodeficiencies that affect the differentiation of mononuclear phagocytes. They also show that human IRF8 is critical for the development of monocytes and dendritic cells and for antimycobacterial immunity. (Funded by the Medical Research Council and others.).


Assuntos
Células Dendríticas/imunologia , Síndromes de Imunodeficiência/genética , Fatores Reguladores de Interferon/genética , Mutação , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos , Vacina BCG/genética , Vacina BCG/imunologia , Feminino , Genes Dominantes , Humanos , Lactente , Fatores Reguladores de Interferon/deficiência , Interleucina-12/biossíntese , Leucócitos Mononucleares/imunologia , Masculino , Modelos Moleculares , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/imunologia , Linhagem , Conformação Proteica , Alinhamento de Sequência
5.
Biol Methods Protoc ; 9(1): bpae046, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38993523

RESUMO

Rapid and accessible testing was paramount in the management of the COVID-19 pandemic. Our university established KCL TEST: a SARS-CoV-2 asymptomatic testing programme that enabled sensitive and accessible PCR testing of SARS-CoV-2 RNA in saliva. Here, we describe our learnings and provide our blueprint for launching diagnostic laboratories, particularly in low-resource settings. Between December 2020 and July 2022, we performed 158277 PCRs for our staff, students, and their household contacts, free of charge. Our average turnaround time was 16 h and 37 min from user registration to result delivery. KCL TEST combined open-source automation and in-house non-commercial reagents, which allows for rapid implementation and repurposing. Importantly, our data parallel those of the UK Office for National Statistics, though we detected a lower positive rate and virtually no delta wave. Our observations strongly support regular asymptomatic community testing as an important measure for decreasing outbreaks and providing safe working spaces. Universities can therefore provide agile, resilient, and accurate testing that reflects the infection rate and trend of the general population. Our findings call for the early integration of academic institutions in pandemic preparedness, with capabilities to rapidly deploy highly skilled staff, as well as develop, test, and accommodate efficient low-cost pipelines.

6.
Blood ; 117(26): 7063-9, 2011 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-21566096

RESUMO

Langerhans cells (LCs) are a distinct population of dendritic cells that form a contiguous network in the epidermis of the skin. Although LCs possess many of the properties of highly proficient dendritic cells, recent studies have indicated that they are not necessary to initiate cutaneous immunity. In this study, we used a tractable model of cutaneous GVHD, induced by topical application of a Toll-like receptor agonist, to explore the role of LCs in the development of tissue injury. By adapting this model to permit inducible and selective depletion of host LCs, we found that GVHD was significantly reduced when LCs were absent. However, LCs were not required either for CD8 T-cell activation within the draining lymph node or subsequent homing of effector cells to the epidermis. Instead, we found that LCs were necessary for inducing transcription of IFN-γ and other key effector molecules by donor CD8 cells in the epidermis, indicating that they license CD8 cells to induce epithelial injury. These data demonstrate a novel regulatory role for epidermal LCs during the effector phase of an inflammatory immune response in the skin.


Assuntos
Comunicação Celular , Citotoxicidade Imunológica , Epiderme/imunologia , Epiderme/patologia , Células de Langerhans/imunologia , Linfócitos T Citotóxicos/imunologia , Aminoquinolinas/toxicidade , Animais , Células Cultivadas , Quimera , Epiderme/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Doença Enxerto-Hospedeiro/imunologia , Granzimas/genética , Granzimas/metabolismo , Imiquimode , Interferon gama/genética , Interferon gama/metabolismo , Células de Langerhans/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Linfócitos T Citotóxicos/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptores Toll-Like/agonistas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
7.
PLoS Pathog ; 3(6): e89, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17604450

RESUMO

An unprecedented epidemic of chikungunya virus (CHIKV) infection recently started in countries of the Indian Ocean area, causing an acute and painful syndrome with strong fever, asthenia, skin rash, polyarthritis, and lethal cases of encephalitis. The basis for chikungunya disease and the tropism of CHIKV remain unknown. Here, we describe the replication characteristics of recent clinical CHIKV strains. Human epithelial and endothelial cells, primary fibroblasts and, to a lesser extent, monocyte-derived macrophages, were susceptible to infection and allowed viral production. In contrast, CHIKV did not replicate in lymphoid and monocytoid cell lines, primary lymphocytes and monocytes, or monocyte-derived dendritic cells. CHIKV replication was cytopathic and associated with an induction of apoptosis in infected cells. Chloroquine, bafilomycin-A1, and short hairpin RNAs against dynamin-2 inhibited viral production, indicating that viral entry occurs through pH-dependent endocytosis. CHIKV was highly sensitive to the antiviral activity of type I and II interferons. These results provide a general insight into the interaction between CHIKV and its mammalian host.


Assuntos
Infecções por Alphavirus/virologia , Vírus Chikungunya/patogenicidade , Doenças Transmissíveis Emergentes/virologia , Replicação Viral , Infecções por Alphavirus/epidemiologia , Vírus Chikungunya/ultraestrutura , Doenças Transmissíveis Emergentes/epidemiologia , Efeito Citopatogênico Viral , Células Endoteliais/patologia , Células Endoteliais/virologia , Células Epiteliais/patologia , Células Epiteliais/virologia , Humanos , Ilhas do Oceano Índico
8.
Science ; 348(6233): 448-53, 2015 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-25814066

RESUMO

Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.


Assuntos
Heterozigoto , Vírus da Influenza A Subtipo H1N1 , Influenza Humana/imunologia , Fator Regulador 7 de Interferon/genética , Interferon Tipo I/biossíntese , Síndrome do Desconforto Respiratório/imunologia , Criança , Células Dendríticas/imunologia , Feminino , Fibroblastos/imunologia , Genes Recessivos , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Influenza Humana/complicações , Influenza Humana/genética , Interferon Tipo I/genética , Leucócitos/imunologia , Pulmão/imunologia , Mutação , Síndrome do Desconforto Respiratório/genética , Síndrome do Desconforto Respiratório/virologia , Mucosa Respiratória/imunologia
9.
PLoS One ; 7(4): e33891, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22506009

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) features inflammatory granuloma characterised by the presence of CD1a+ dendritic cells or 'LCH cells'. Badalian-Very et al. recently reported the presence of a canonical (V600E)B-RAF mutation in 57% of paraffin-embedded biopsies from LCH granuloma. Here we confirm their findings and report the identification of two novel B-RAF mutations detected in LCH patients. METHODS AND RESULTS: Mutations of B-RAF were observed in granuloma samples from 11 out of 16 patients using 'next generation' pyrosequencing. In 9 cases the mutation identified was (V600E)B-RAF. In 2 cases novel polymorphisms were identified. A somatic (600DLAT)B-RAF insertion mimicked the structural and functional consequences of the (V600E)B-RAF mutant. It destabilized the inactive conformation of the B-RAF kinase and resulted in increased ERK activation in 293 T cells. The (600DLAT)B-RAF and (V600E)B-RAF mutations were found enriched in DNA and mRNA from the CD1a+ fraction of granuloma. They were absent from the blood and monocytes of 58 LCH patients, with a lower threshold of sequencing sensitivity of 1%-2% relative mutation abundance. A novel germ line (T599A)B-RAF mutant allele was detected in one patient, at a relative mutation abundance close to 50% in the LCH granuloma, blood monocytes and lymphocytes. However, (T599A)B-RAF did not destabilize the inactive conformation of the B-RAF kinase, and did not induce increased ERK phosphorylation or C-RAF transactivation. CONCLUSIONS: Our data confirmed presence of the (V600E)B-RAF mutation in LCH granuloma of some patients, and identify two novel B-RAF mutations. They indicate that (V600E)B-RAF and (600DLAT)B-RAF mutations are somatic mutants enriched in LCH CD1a(+) cells and absent from the patient blood. Further studies are needed to assess the functional consequences of the germ-line (T599A)B-RAF allele.


Assuntos
Granuloma/genética , Histiocitose de Células de Langerhans/enzimologia , Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Alelos , Sequência de Aminoácidos , Criança , Pré-Escolar , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Predisposição Genética para Doença , Granuloma/metabolismo , Células HEK293 , Histiocitose de Células de Langerhans/metabolismo , Humanos , Lactente , Linfócitos/metabolismo , Masculino , Dados de Sequência Molecular , Monócitos/metabolismo , Fosforilação/genética , Polimorfismo Genético , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas c-raf/metabolismo , Homologia de Sequência de Aminoácidos , Ativação Transcricional , Adulto Jovem
10.
J Clin Invest ; 122(3): 821-32, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22354167

RESUMO

Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56(dim) NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients' fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients' growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56(dim) subset in patients was associated with a lower rate of NK CD56(bright) cell proliferation, and the maturation of NK CD56(bright) cells toward an NK CD56(dim) phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency.


Assuntos
Insuficiência Adrenal/genética , Proteínas de Ciclo Celular/genética , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Transtornos do Crescimento/genética , Células Matadoras Naturais/citologia , Proteínas Nucleares/genética , Alelos , Animais , Proteínas de Ciclo Celular/deficiência , Criança , Pré-Escolar , DNA Helicases/deficiência , Replicação do DNA , Proteínas de Ligação a DNA/deficiência , Fibroblastos/metabolismo , Regulação da Expressão Gênica , Teste de Complementação Genética , Ligação Genética , Predisposição Genética para Doença , Homozigoto , Humanos , Lactente , Camundongos , Componente 4 do Complexo de Manutenção de Minicromossomo , Mutação , Proteínas Nucleares/deficiência , Linhagem
11.
Curr Biol ; 21(19): 1672-7, 2011 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-21962711

RESUMO

TGF-ß superfamily signals play complex roles in regulation of tissue repair and inflammation in mammals [1]. Drosophila melanogaster is a well-established model for the study of innate immune function [2, 3] and wound healing [4-7]. Here, we explore the role and regulation of two TGF-ß superfamily members, dawdle and decapentaplegic (dpp), in response to wounding and infection in adult Drosophila. We find that both TGF-ß signals exhibit complex regulation in response to wounding and infection, each is expressed in a subset of phagocytes, and each inhibits a specific arm of the immune response. dpp is rapidly activated by wounds and represses the production of antimicrobial peptides; flies lacking dpp function display persistent, strong antimicrobial peptide expression after even a small wound. dawdle, in contrast, is activated by Gram-positive bacterial infection but repressed by Gram-negative infection or wounding; its role is to limit infection-induced melanization. Flies lacking dawdle function exhibit melanization even when uninfected. Together, these data imply a model in which the bone morphogenetic protein (BMP) dpp is an important inhibitor of inflammation following sterile injury whereas the activin-like dawdle determines the nature of the induced immune response.


Assuntos
Proteínas de Transporte/imunologia , Proteínas de Drosophila/imunologia , Drosophila melanogaster/imunologia , Imunidade Inata , Transdução de Sinais , Animais , Soluções Tampão , Proteínas de Transporte/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Resposta ao Choque Térmico , Micrococcus luteus/imunologia , Fosfatos/química , Cloreto de Sódio/química
12.
J Exp Med ; 206(3): 595-606, 2009 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-19273628

RESUMO

CX(3)CR1 expression is associated with the commitment of CSF-1R(+) myeloid precursors to the macrophage/dendritic cell (DC) lineage. However, the relationship of the CSF-1R(+) CX(3)CR1(+) macrophage/DC precursor (MDP) with other DC precursors and the role of CX(3)CR1 in macrophage and DC development remain unclear. We show that MDPs give rise to conventional DCs (cDCs), plasmacytoid DCs (PDCs), and monocytes, including Gr1(+) inflammatory monocytes that differentiate into TipDCs during infection. CX(3)CR1 deficiency selectively impairs the recruitment of blood Gr1(+) monocytes in the spleen after transfer and during acute Listeria monocytogenes infection but does not affect the development of monocytes, cDCs, and PDCs.


Assuntos
Células Dendríticas/enzimologia , Inflamação/enzimologia , Macrófagos/enzimologia , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptores de Quimiocinas/metabolismo , Células-Tronco/enzimologia , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Receptor 1 de Quimiocina CX3C , Diferenciação Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Células Dendríticas/citologia , Células Dendríticas/imunologia , Inflamação/imunologia , Listeria monocytogenes , Listeriose/imunologia , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Monócitos/citologia , Monócitos/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Quimiocinas/deficiência , Baço/citologia , Baço/imunologia , Baço/microbiologia , Células-Tronco/citologia , Células-Tronco/imunologia , Fator de Necrose Tumoral alfa/biossíntese
13.
EMBO J ; 26(2): 516-26, 2007 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-17215865

RESUMO

HIV efficiently spreads in lymphocytes, likely through virological synapses (VSs). These cell-cell junctions share some characteristics with immunological synapses, but cellular proteins required for their constitution remain poorly characterized. We have examined here the role of ZAP-70, a key kinase regulating T-cell activation and immunological synapse formation, in HIV replication. In lymphocytes deficient for ZAP-70, or expressing a kinase-dead mutant of the protein, HIV replication was strikingly delayed. We have characterized further this replication defect. ZAP-70 was dispensable for the early steps of viral cycle, from entry to expression of viral proteins. However, in the absence of ZAP-70, intracellular Gag localization was impaired. ZAP-70 was required in infected donor cells for efficient cell-to-cell HIV transmission to recipients and for formation of VSs. These results bring novel insights into the links that exist between T-cell activation and HIV spread, and suggest that HIV usurps components of the immunological synapse machinery to ensure its own spread through cell-to-cell contacts.


Assuntos
Comunicação Celular , HIV/fisiologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Proteína-Tirosina Quinase ZAP-70/fisiologia , Células Cultivadas , Células HeLa , Humanos , Lactente , Células Jurkat , Replicação Viral , Proteína-Tirosina Quinase ZAP-70/genética
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