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1.
iScience ; 25(10): 105066, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36093378

RESUMO

Patients with severe COVID-19 show an altered immune response that fails to control the viral spread and suffer from exacerbated inflammatory response, which eventually can lead to death. A major challenge is to develop an effective treatment for COVID-19. NF-κB is a major player in innate immunity and inflammatory process. By a high-throughput screening approach, we identified FDA-approved compounds that inhibit the NF-κB pathway and thus dampen inflammation. Among these, we show that Auranofin prevents post-translational modifications of NF-κB effectors and their recruitment into activating complexes in response to SARS-CoV-2 infection or cytokine stimulation. In addition, we demonstrate that Auranofin counteracts several steps of SARS-CoV-2 infection. First, it inhibits a raft-dependent endocytic pathway involved in SARS-CoV-2 entry into host cells; Second, Auranofin alters the ACE2 mobility at the plasma membrane. Overall, Auranofin should prevent SARS-CoV-2 infection and inflammatory damages, offering new opportunities as a repurposable drug candidate to treat COVID-19.

2.
PLoS Pathog ; 15(5): e1007758, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095640

RESUMO

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Proteínas de Transporte/metabolismo , Infecções por HIV/metabolismo , HIV-2/imunologia , Memória Imunológica/imunologia , Leucócitos Mononucleares/metabolismo , Receptores CXCR6/metabolismo , Adulto , Idoso , Fatores de Restrição Antivirais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , Proteínas de Transporte/genética , Estudos de Casos e Controles , Células Cultivadas , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-2/genética , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR6/genética , Transcriptoma , Proteínas com Motivo Tripartido , Ubiquitina-Proteína Ligases
3.
Blood ; 129(7): 855-865, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-28060720

RESUMO

Human herpesvirus 8 (HHV-8) is the causative agent of Kaposi sarcoma (KS) and multicentric Castleman disease (MCD), a life-threatening, virally induced B-cell lymphoproliferative disorder. HHV-8 is a B-lymphotropic γ-herpesvirus closely related to the Epstein-Barr virus (EBV). Invariant natural killer T (iNKT) cells are innate-like T cells that play a role in antiviral immunity, specifically in controlling viral replication in EBV-infected B cells. Decline of iNKT cells is associated with age or HIV infection, both situations associated with HHV-8-related diseases. We analyzed iNKT cells in both blood (n = 26) and spleen (n = 9) samples from 32 patients with HHV-8 MCD and compared them with patients with KS (n = 24) and healthy donors (n = 29). We determined that both circulating and splenic iNKT cell frequencies were markedly decreased in patients with HHV-8 MCD and were undetectable in 6 of them. Moreover, iNKT cells from patients with HHV-8 MCD displayed a proliferative defect after stimulation with α-galactosylceramide. These iNKT cell alterations were associated with an imbalance in B-cell subsets, including a significant decrease in memory B cells, particularly of marginal zone (MZ) B cells. Coculture experiments revealed that the decrease in iNKT cells contributed to the alterations in the B-cell subset distribution. These observations contribute to a better understanding of the complex interactions between HHV-8 and immune cells that cause HHV-8-related MCD.


Assuntos
Subpopulações de Linfócitos B/patologia , Hiperplasia do Linfonodo Gigante/patologia , Hiperplasia do Linfonodo Gigante/virologia , Herpesvirus Humano 8/isolamento & purificação , Células T Matadoras Naturais/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD1d/análise , Subpopulações de Linfócitos B/virologia , Proliferação de Células , Feminino , Humanos , Imunoglobulina D/análise , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/virologia , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/virologia , Baço/patologia , Baço/virologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/análise
4.
AIDS ; 28(11): 1567-77, 2014 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-24804861

RESUMO

OBJECTIVES: The aim of the study was to determine the molecular mechanisms underlying the quasi-equilibrium between HIV and its host in the model of functional cure represented by elite controllers who spontaneously maintain exceptionally low levels of HIV reservoirs. DESIGN: Whole-genome transcriptional study and quantification of the cell-associated HIV DNA and HIV RNA levels of the four major resting CD4 T-cell subsets in HIV-1-infected elite controllers, viremic long-term nonprogressors (vir-LTNPs), and uninfected individuals. METHODS: We compared the whole-genome transcriptional profiles (ArrayExpress accession number E-MTAB-1480) of the four major resting CD4 T-cell subsets [naive (TN), central-memory (TCM), transitional-memory (TTM), and effector-memory (TEM)] from 14 HIV-1-infected individuals including seven elite controllers (E-LTNPs) and seven vir-LTNPs, and from seven uninfected individuals. The HIV-1 cellular DNA and mRNA levels were quantified in parallel in each sorted subset. RESULTS: Host gene transcriptomes followed subset differentiation and viremia except in E-LTNPs wherein TCM, the main CD4 cell compartment, showed the highest activity with three specific signatures involving overexpression of T-cell receptor and costimulation signaling pathways, overexpression of the PRDM-1/Blimp-1 transcriptional repressor, and downmodulation of type-I IFN-related genes. Among subsets, the PRDM1/Blimp-1 upregulation was associated with lower levels of both cellular HIV-DNA and HIV mRNA levels. CONCLUSION: This unique Blimp-1 transcriptional repressor signature and the contrast between host and virus transcriptional activities in TCM from elite controllers suggest Blimp-1 might be involved in controlling the HIV reservoirs in the key TCM subset.


Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Proteínas Repressoras/metabolismo , Transcrição Gênica , Latência Viral , Adulto , Idoso , Animais , Linfócitos T CD4-Positivos/imunologia , DNA Viral/análise , DNA Viral/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Infecções por HIV/virologia , Sobreviventes de Longo Prazo ao HIV , Humanos , Masculino , Pessoa de Meia-Idade , Fator 1 de Ligação ao Domínio I Regulador Positivo , RNA Viral/análise , RNA Viral/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/virologia
5.
Viral Immunol ; 22(6): 467-72, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19951185

RESUMO

We are currently facing a global threat caused by a highly pathogenic avian H5N1 influenza virus (hpH5N1). Death occurs in 48 h in infected chickens, suggesting that they fail to eliminate the virus. Little is known about the immune response in chickens after hpH5N1 infection, or how the virus is evolving to modify and evade host protective responses. Therefore, to better understand the chicken immune response following hpH5N1 infection, we set up an experimental infection of chickens with an hpH5N1 strain, and quantified the mRNA expression of several cytokines and antiviral proteins at different time points post-infection. We show here that a weak host immune response is observed in vivo, in spite of the induction of IL-6, myxovirus resistance protein (Mx), and protein kinase R (PKR). This weak immune response, probably due in part to the absence of type I interferon, was not sufficient to counteract the hpH5N1 virus and protect the chicken from death.


Assuntos
Galinhas/imunologia , Proteínas de Ligação ao GTP/fisiologia , Evasão da Resposta Imune , Virus da Influenza A Subtipo H5N1/patogenicidade , Influenza Aviária/imunologia , Proteínas Quinases/fisiologia , Animais , Galinhas/virologia , Citocinas/biossíntese , Citocinas/genética , Feminino , Proteínas de Ligação ao GTP/biossíntese , Proteínas de Ligação ao GTP/genética , Regulação da Expressão Gênica , Imunidade Inata/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Influenza Aviária/prevenção & controle , Intestinos/virologia , Pulmão/virologia , Proteínas de Resistência a Myxovirus , Especificidade de Órgãos , Proteínas Quinases/biossíntese , Proteínas Quinases/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Viral/análise , Baço/virologia , Virulência
6.
Immunogenetics ; 61(1): 55-70, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19009289

RESUMO

Recent large-scale cDNA cloning studies have shown that a significant proportion of the transcripts expressed from vertebrate genomes do not appear to encode protein. Moreover, it was reported in mammals (human and mice) that these non-coding transcripts are expressed and regulated by mechanisms similar to those involved in the control of protein-coding genes. We have produced a collection of cDNA sequences from immunologically active tissues with the aim of discovering chicken genes involved in immune mechanisms, and we decided to explore the non-coding component of these immune-related libraries. After finding known non-coding RNAs (miRNA, snRNA, snoRNA), we identified new putative mRNA-like non-coding RNAs. We characterised their expression profiles in immune-related samples. Some of them showed changes in expression following viral infections. As they exhibit patterns of expression that parallel the behaviour of protein-coding RNAs in immune tissues, our study suggests that they could play an active role in the immune response.


Assuntos
Galinhas/genética , DNA Complementar/genética , RNA não Traduzido/genética , Animais , Infecções por Birnaviridae/genética , Infecções por Birnaviridae/imunologia , Galinhas/imunologia , Etiquetas de Sequências Expressas , Feminino , Perfilação da Expressão Gênica , Biblioteca Gênica , Ativação Linfocitária , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Masculino , Doença de Marek/genética , Doença de Marek/imunologia , MicroRNAs/genética , MicroRNAs/isolamento & purificação , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Especificidade de Órgãos , RNA não Traduzido/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Homologia de Sequência do Ácido Nucleico , Especificidade da Espécie , Linfócitos T/imunologia
7.
J Virol ; 80(18): 9207-16, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16940532

RESUMO

Using a novel cDNA microarray prepared from sources of actively responding immune system cells, we have investigated the changes in gene expression in the target tissue during the early stages of infection of neonatal chickens with infectious bursal disease virus. Infections of two lines of chickens previously documented as genetically resistant and sensitive to infection were compared in order to ascertain early differences in the response to infection that might provide clues to the mechanism of differential genetic resistance. In addition to major changes that could be explained by previously described changes in infected tissue, some differences in gene expression on infection, and differences between the two chicken lines, were observed that led to a model for resistance in which a more rapid inflammatory response and more-extensive p53-related induction of apoptosis in the target B cells might limit viral replication and consequent pathology. Ironically, the effect in the asymptomatic neonatal infection is that more-severe B-cell depletion is seen in the more genetically resistant chicken. Changes of expression of many chicken genes of unknown function, indicating possible roles in the response to infection, may aid in the functional annotation of these genes.


Assuntos
Predisposição Genética para Doença , Inflamação , Transcrição Gênica , Viroses/etiologia , Viroses/genética , Animais , Apoptose , Galinhas , DNA Complementar/metabolismo , Eimeria tenella/metabolismo , Perfilação da Expressão Gênica , Sistema Imunitário , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Proteína Supressora de Tumor p53/metabolismo
8.
Immunogenetics ; 57(1-2): 116-28, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15744538

RESUMO

We have identified and characterised a cluster of six TRIM-B30.2 genes flanking the chicken BF/BL region of the B complex. The TRIM-B30.2 proteins are a subgroup of the TRIM protein family containing the tripartite motif (TRIM), consisting of a RING domain, a B-box and a coiled coil region, and a B30.2-like domain. In humans, a cluster of seven TRIM-B30.2 genes has been characterised within the MHC on Chromosome 6p21.33. Among the six chicken TRIM-B30.2 genes two are orthologous to those of the human MHC, and two (TRIM41 and TRIM7) are orthologous to human genes located on Chromosome 5. In humans, these last two genes are adjacent to GNB2L1, a guanine nucleotide-binding protein gene, the ortholog of the chicken c12.3 gene situated in the vicinity of the TRIM-B30.2 genes. This suggests that breakpoints specific to mammals have occurred and led to the remodelling of their MHC structure. In terms of structure, like their mammalian counterparts, each chicken gene consists of five coding exons; exon 1 encodes the RING domain and the B-box, exons 2, 3 and 4 form the coiled-coil region, and the last exon represents the B30.2-like domain. Phylogenetic analysis led us to assume that this extended BF/BL region may be similar to the human extended class I region, because it contains a cluster of BG genes sharing an Ig-V like domain with the BTN genes (Henry et al. 1997a) and six TRIM-B30.2 genes containing the B30.2-like domain, shared with the TRIM-B30.2 members and the BTN genes.


Assuntos
Galinhas/genética , Genes MHC Classe I , Família Multigênica , Sequência de Aminoácidos , Animais , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Dados de Sequência Molecular , Filogenia , Estrutura Secundária de Proteína , Alinhamento de Sequência
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