Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.568
Filtrar
2.
Arch Virol ; 166(4): 1007-1013, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33547957

RESUMO

Porcine endogenous retroviruses (PERVs) are integrated in the genome of all pigs, and they produce viral particles that are able to infect human cells and therefore pose a special risk for xenotransplantation. In contrast to other pig microorganisms that also pose a risk, such as porcine cytomegalovirus and hepatitis E virus, PERVs cannot be eliminated from pigs by vaccines, antiviral drugs, early weaning, or embryo transfer. Since PERVs are relevant for xenotransplantation, their biology and origin are of great interest. Recent studies have shown that PERVs are the result of a transspecies transmission of precursor retroviruses from different animals and further evolution in the pig genome. PERVs acquired different long terminal repeats (LTRs), and recombination took place. In parallel, it has been shown that the activity of the LTRs and recombination in the envelope are important for the transmissibility and pathogenesis of PERVs. Transspecies transmission of retroviruses is common, a well-known example being the transmission of precursor retroviruses from non-human primates to humans, resulting in human immunodeficiency virus (HIV). Here, recent findings concerning the origin of PERVs, their LTRs, and recombination events that occurred during evolution are reviewed and compared with other findings regarding transspecies transmission of retroviruses.


Assuntos
Retrovirus Endógenos/genética , Evolução Molecular , Suínos/virologia , Animais , Retrovirus Endógenos/classificação , Genoma Viral , Humanos , Prevalência , Recombinação Genética , Retroviridae/classificação , Retroviridae/genética , Zoonoses/transmissão , Zoonoses/virologia
3.
Nat Rev Microbiol ; 19(3): 138-139, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33469167
4.
Arch Virol ; 166(3): 831-840, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33486631

RESUMO

Ovine pulmonary adenomatosis (OPA) is caused by jaagsiekte sheep retrovirus (JSRV) and is a chronic, progressive, and infectious neoplastic lung disease in sheep, which causes significant economic losses to the sheep industry. Neither a vaccine nor serological diagnostic methods to detect OPA are available. We performed a JSRV infection survey in sheep using blood samples (n = 1,372) collected in the three northeastern provinces of China (i.e., Inner Mongolia, Heilongjiang, and Jilin) to determine JSRV infection status in sheep herds using a real-time PCR assay targeting the gag gene of JSRV. The ovine endogenous retrovirus sequence was successfully amplified in all sheep samples tested (296 from the Inner Mongolia Autonomous Region, 255 from Jilin province, and 821 from Heilongjiang province). Subsequently, we attempted to distinguish exogenous JSRV (exJSRV) and endogenous JSRV (enJSRV) infections in these JSRV-positive samples using a combination assay that identifies a ScaI restriction site in an amplified 229-bp fragment of the gag gene of JSRV and a "LHMKYXXM" motif in the cytoplasmic tail region of the JSRV envelope protein. The ScaI restriction site is present in all known oncogenic JSRVs but absent in ovine endogenous retroviruses, while the "LHMKYXXM" motif is in all known exJSRVs but not in enJSRVs. Interestingly, one JSRV strain (HH13) from Heilongjiang province contained the "LHMKYXXM" motif but not the ScaI enzyme site. Phylogenetic analysis showed that strain HH13 was closely related to strain enJSRV-21 reported in the USA, indicating that HH13 could be an exogenous virus. Our results provide valuable information for further research on the genetic evolution and pathogenesis of JSRV.


Assuntos
Retrovirus Endógenos/genética , Produtos do Gene env/genética , Retrovirus Jaagsiekte de Ovinos/genética , Adenomatose Pulmonar Ovina/epidemiologia , Adenomatose Pulmonar Ovina/patologia , Motivos de Aminoácidos/genética , Animais , Sequência de Bases , China/epidemiologia , DNA Viral/análise , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Evolução Molecular , Genoma Viral/genética , Retrovirus Jaagsiekte de Ovinos/classificação , Filogenia , Reação em Cadeia da Polimerase em Tempo Real , Mapeamento por Restrição , Homologia de Sequência do Ácido Nucleico , Ovinos
5.
Nat Commun ; 11(1): 5660, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168830

RESUMO

Human endogenous retroviruses (HERV) form a substantial part of the human genome, but mostly remain transcriptionally silent under strict epigenetic regulation, yet can potentially be reactivated by malignant transformation or epigenetic therapies. Here, we evaluate the potential for T cell recognition of HERV elements in myeloid malignancies by mapping transcribed HERV genes and generating a library of 1169 potential antigenic HERV-derived peptides predicted for presentation by 4 HLA class I molecules. Using DNA barcode-labeled MHC-I multimers, we find CD8+ T cell populations recognizing 29 HERV-derived peptides representing 18 different HERV loci, of which HERVH-5, HERVW-1, and HERVE-3 have more profound responses; such HERV-specific T cells are present in 17 of the 34 patients, but less frequently in healthy donors. Transcriptomic analyses reveal enhanced transcription of the HERVs in patients; meanwhile DNA-demethylating therapy causes a small and heterogeneous enhancement in HERV transcription without altering T cell recognition. Our study thus uncovers T cell recognition of HERVs in myeloid malignancies, thereby implicating HERVs as potential targets for immunotherapeutic therapies.


Assuntos
Retrovirus Endógenos/genética , Neoplasias Hematológicas/virologia , Linfócitos T/metabolismo , Linfócitos T/virologia , Linfócitos T CD8-Positivos , Epigênese Genética , Epitopos de Linfócito T , Perfilação da Expressão Gênica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Humanos , Imunoterapia , Monitorização Imunológica , Células Mieloides , Neoplasias
6.
Nucleic Acids Res ; 48(19): 10890-10908, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-33021676

RESUMO

Although endogenous retroviruses (ERVs) are known to harbor cis-regulatory elements, their role in modulating cellular immune responses remains poorly understood. Using an RNA-seq approach, we show that several members of the ERV9 lineage, particularly LTR12C elements, are activated upon HIV-1 infection of primary CD4+ T cells. Intriguingly, HIV-1-induced ERVs harboring transcription start sites are primarily found in the vicinity of immunity genes. For example, HIV-1 infection activates LTR12C elements upstream of the interferon-inducible genes GBP2 and GBP5 that encode for broad-spectrum antiviral factors. Reporter assays demonstrated that these LTR12C elements drive gene expression in primary CD4+ T cells. In line with this, HIV-1 infection triggered the expression of a unique GBP2 transcript variant by activating a cryptic transcription start site within LTR12C. Furthermore, stimulation with HIV-1-induced cytokines increased GBP2 and GBP5 expression in human cells, but not in macaque cells that naturally lack the GBP5 gene and the LTR12C element upstream of GBP2. Finally, our findings suggest that GBP2 and GBP5 have already been active against ancient viral pathogens as they suppress the maturation of the extinct retrovirus HERV-K (HML-2). In summary, our findings uncover how human cells can exploit remnants of once-infectious retroviruses to regulate antiviral gene expression.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Retrovirus Endógenos/genética , Regulação da Expressão Gênica/imunologia , Infecções por HIV/genética , Regiões Promotoras Genéticas , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/imunologia , Células HEK293 , Infecções por HIV/imunologia , HIV-1 , Humanos , Macaca mulatta , Subpopulações de Linfócitos T/citologia
7.
Nucleic Acids Res ; 48(18): 10211-10225, 2020 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-32894293

RESUMO

Endogenous retroviruses (ERVs) were usually silenced by various histone modifications on histone H3 variants and respective histone chaperones in embryonic stem cells (ESCs). However, it is still unknown whether chaperones of other histones could repress ERVs. Here, we show that H2A/H2B histone chaperone FACT plays a critical role in silencing ERVs and ERV-derived cryptic promoters in ESCs. Loss of FACT component Ssrp1 activated MERVL whereas the re-introduction of Ssrp1 rescued the phenotype. Additionally, Ssrp1 interacted with MERVL and suppressed cryptic transcription of MERVL-fused genes. Remarkably, Ssrp1 interacted with and recruited H2B deubiquitinase Usp7 to Ssrp1 target genes. Suppression of Usp7 caused similar phenotypes as loss of Ssrp1. Furthermore, Usp7 acted by deubiquitinating H2Bub and thereby repressed the expression of MERVL-fused genes. Taken together, our study uncovers a unique mechanism by which FACT complex silences ERVs and ERV-derived cryptic promoters in ESCs.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Retrovirus Endógenos/genética , Proteínas de Grupo de Alta Mobilidade/fisiologia , Chaperonas de Histonas/fisiologia , Regiões Promotoras Genéticas , Fatores de Transcrição/fisiologia , Animais , Linhagem Celular , Regulação da Expressão Gênica , Histonas/metabolismo , Camundongos , Células-Tronco Embrionárias Murinas , Peptidase 7 Específica de Ubiquitina/fisiologia
8.
Nat Commun ; 11(1): 3506, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32665538

RESUMO

Acute myeloid leukemia (AML) is characterised by a series of genetic and epigenetic alterations that result in deregulation of transcriptional networks. One understudied source of transcriptional regulators are transposable elements (TEs), whose aberrant usage could contribute to oncogenic transcriptional circuits. However, the regulatory influence of TEs and their links to AML pathogenesis remain unexplored. Here we identify six endogenous retrovirus (ERV) families with AML-associated enhancer chromatin signatures that are enriched in binding of key regulators of hematopoiesis and AML pathogenesis. Using both locus-specific genetic editing and simultaneous epigenetic silencing of multiple ERVs, we demonstrate that ERV deregulation directly alters the expression of adjacent genes in AML. Strikingly, deletion or epigenetic silencing of an ERV-derived enhancer suppresses cell growth by inducing apoptosis in leukemia cell lines. This work reveals that ERVs are a previously unappreciated source of AML enhancers that may be exploited by cancer cells to help drive tumour heterogeneity and evolution.


Assuntos
Cromatina/metabolismo , Leucemia Mieloide Aguda/genética , Animais , Linhagem Celular , Cromatina/genética , Elementos de DNA Transponíveis/genética , Retrovirus Endógenos/genética , Epigênese Genética/genética , Redes Reguladoras de Genes/genética , Redes Reguladoras de Genes/fisiologia , Genoma Humano/genética , Humanos , Sequências Repetitivas Dispersas/genética
9.
Genet Sel Evol ; 52(1): 29, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487054

RESUMO

BACKGROUND: Avian leukosis virus subgroup E (ALVE) insertions are endogenous retroviruses (ERV) that are restricted to the domestic chicken and its wild progenitor. In commercial chickens, ALVE are known to have a detrimental effect on productivity and provide a source for recombination with exogenous retroviruses. The wider diversity of ALVE in non-commercial chickens and the role of these elements in ERV-derived immunity (EDI) are yet to be investigated. RESULTS: In total, 974 different ALVE were identified from 407 chickens sampled from village populations in Ethiopia, Iraq, and Nigeria, using the recently developed obsERVer bioinformatics identification pipeline. Eighty-eight percent of all identified ALVE were novel, bringing the known number of ALVE integrations to more than 1300 across all analysed chickens. ALVE content was highly lineage-specific and populations generally exhibited a large diversity of ALVE at low frequencies, which is typical for ERV involved in EDI. A significantly larger number of ALVE was found within or near coding regions than expected by chance, although a relative depletion of ALVE was observed within coding regions, which likely reflects selection against deleterious integrations. These effects were less pronounced than in previous analyses of chickens from commercial lines. CONCLUSIONS: Identification of more than 850 novel ALVE has trebled the known diversity of these retroviral elements. This work provides the basis for future studies to fully quantify the role of ALVE in immunity against exogenous ALV, and development of programmes to improve the productivity and welfare of chickens in developing economies.


Assuntos
Vírus da Leucose Aviária/genética , Animais , Animais Selvagens , Galinhas/virologia , Retrovirus Endógenos/genética , Etiópia , Variação Genética/genética , Iraque , Nigéria
10.
PLoS One ; 15(5): e0233066, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433714

RESUMO

DNA replicase polymerase ε (POLE) is critical in proofreading and correcting errors of DNA replication. Low POLE expression plays a pivotal role in accumulation of mutations and onset of cancer, contributing to development and growth of tumor cells. The aim of this study is to reveal the survival, alternative genes and antitumoral immune activities in non-small cell lung cancer (NSCLC) patients with low POLE expression and provide treatment strategies that can increase their survival rates. This study investigated the clinicopathologic parameters, various tumor-infiltrating lymphocytes (TILs), endogenous retrovirus, molecular interactions and in vitro drug screen according to POLE mutation/expression in 168 and 1,019 NSCLC patients from the Konkuk University Medical Center (KUMC) and the Cancer Genome Atlas, respectively. We identified mutations of 75 genes in the sequencing panels, with POLE frame shift p.V1446fs being the most frequent (56.8%) in KUMC based on 170 targeted sequencing panels. Mutant and high expression of POLE correlated with favorable prognosis with increased TILs and tumor mutation burden, compared with wild type and low expression of POLE. We found specific molecular interactions associated with cell cycle and antigen presentation. An in vitro drug screen identified dasatinib that inhibited growth of the NSCLC cell line with low POLE expression. POLE could contribute to the future development of anticancer drugs for patients with NSCLC.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , DNA Polimerase II/genética , Mutação da Fase de Leitura , Neoplasias Pulmonares/mortalidade , Proteínas de Ligação a Poli-ADP-Ribose/genética , Regulação para Cima , Apresentação do Antígeno , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dasatinibe/farmacologia , Retrovirus Endógenos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Prognóstico , Análise de Sobrevida
11.
Cancer Res ; 80(12): 2441-2450, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32245794

RESUMO

The DNA methyltransferase inhibitors (DNMTi) 5-azacytidine and 5-aza-2-deoxycytidine have been approved for the treatment of different types of hematologic malignancies. However, only about 50% of patients respond to treatment. Therefore, a more comprehensive understanding of the molecular changes in patients treated with DNMTi is needed. Here, we examined gene expression profiles in a total of 150 RNA samples from two adult cohorts and one pediatric cohort with hematologic cancers taken before, during, and after treatment with 5-azacytidine (40 patients; 15 nonresponders, 25 responders). Using each patient as their own control, malignant cells showed preferential activation of a subset of evolutionarily young transposable elements (TE), including endogenous retroviral long terminal repeats (LTR), short and long interspersed nuclear elements (SINE and LINE), and the type I IFN pathway in responders, all independent of disease classification. Transfection of eight upregulated LTRs into recipient human cells in culture showed robust and heterogenous activation of six genes in the type I IFN pathway. These results, obtained in diverse hematologic disease entities, show that common targets (TE) activated by the same drug (5-azacytidine) elicit an immune response, which may be important for patient's responses to DNMTi. SIGNIFICANCE: Activation of specific classes of evolutionarily young transposable elements can lead to activation of the innate immune system.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Azacitidina/farmacologia , Elementos de DNA Transponíveis/efeitos dos fármacos , Neoplasias Hematológicas/tratamento farmacológico , Imunidade Inata/genética , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Estudos de Coortes , Elementos de DNA Transponíveis/genética , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/imunologia , Retrovirus Endógenos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Interferon Tipo I/metabolismo , Masculino , Pessoa de Meia-Idade , Mimetismo Molecular/imunologia , RNA-Seq , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Regulação para Cima/efeitos dos fármacos
12.
Med Sci (Paris) ; 36(3): 253-260, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-32228844

RESUMO

Upon priming by dendritic cells, naïve CD4 T lymphocytes are exposed to distinct molecular environments depending on the nature of the pathological stimulus. In response, they mobilize different gene networks that establish lineage-specific developmental programs, and coordinate the acquisition of specific phenotype and functions. Accordingly, CD4 T cells are capable of differentiation into a large variety of functionally-distinct T helper (Th) cell subsets. In this review, we describe the molecular events that control CD4 T cell differentiation at the level of the chromatin. We insist on recent works that have highlighted the key role of H3K9me3-dependent epigenetic mechanisms in the regulation of T cell identity. Interestingly, these pathways shape and control the developmental programs at least in part through the regulation of endogenous retroviruses-derived sequences that have been exapted into cis-regulatory modules of Th genes.


Assuntos
Retrovirus Endógenos/fisiologia , Fenômenos do Sistema Imunológico/fisiologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Epigênese Genética/fisiologia , Humanos , Ativação Linfocitária/fisiologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/fisiologia
13.
Proc Natl Acad Sci U S A ; 117(11): 5987-5996, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123111

RESUMO

Endogenous retroviruses and long terminal repeat (LTR) retrotransposons are mobile genetic elements that are closely related to retroviruses. Desilenced endogenous retroviruses are associated with human autoimmune disorders and neurodegenerative diseases. Caenorhabditis elegans and related Caenorhabditis spp. contain LTR retrotransposons and, as described here, numerous integrated viral genes including viral envelope genes that are part of LTR retrotransposons. We found that both LTR retrotransposons and endogenous viral elements are silenced by ADARs [adenosine deaminases acting on double-stranded RNA (dsRNA)] together with the endogenous RNA interference (RNAi) factor ERI-6/7, a homolog of MOV10 helicase, a retrotransposon and retrovirus restriction factor in human. siRNAs corresponding to integrated viral genes and LTR retrotransposons, but not to DNA transposons, are dependent on the ADARs and ERI-6/7. siRNAs corresponding to palindromic repeats are independent of the ADARs and ERI-6/7, and are in fact increased in adar- and eri-6/7-defective mutants because of an antiviral RNAi response to dsRNA. Silencing of LTR retrotransposons is dependent on downstream RNAi factors and P granule components but is independent of the viral sensor DRH-1/RIG-I and the nuclear Argonaute NRDE-3. The activation of retrotransposons in the ADAR- and ERI-6/7/MOV10-defective mutant is associated with the induction of the unfolded protein response (UPR), a common response to viral infection. The overlap between genes induced upon viral infection and infection with intracellular pathogens and genes coexpressed with retrotransposons suggests that there is a common response to different types of foreign elements that includes a response to proteotoxicity presumably caused by the burden of replicating pathogens and expressed retrotransposons.


Assuntos
Caenorhabditis elegans/genética , Retrovirus Endógenos/genética , Interações entre Hospedeiro e Microrganismos/genética , Interferência de RNA , Retroelementos/genética , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Animais , Caenorhabditis elegans/virologia , Proteínas de Caenorhabditis elegans/metabolismo , DNA Helicases/metabolismo , DNA Viral/metabolismo , Estresse do Retículo Endoplasmático/genética , Regulação Viral da Expressão Gênica , Genes Virais/genética , Humanos , RNA de Cadeia Dupla/metabolismo , RNA Viral/metabolismo , Homologia de Sequência de Aminoácidos , Sequências Repetidas Terminais/genética , Resposta a Proteínas não Dobradas/genética
14.
Crit Care ; 24(1): 96, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188504

RESUMO

BACKGROUND: Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Numerous studies have explored the complex and dynamic transcriptome modulations observed in sepsis patients, but a large fraction of the transcriptome remains unexplored. This fraction could provide information to better understand sepsis pathophysiology. Multiple levels of interaction between human endogenous retroviruses (HERV) and the immune response have led us to hypothesize that sepsis is associated with HERV transcription and that HERVs may contribute to a signature among septic patients allowing stratification and personalized management. METHODS: We used a high-density microarray and RT-qPCR to evaluate the HERV and Mammalian Apparent Long Terminal Repeat retrotransposons (MaLR) transcriptome in a pilot study that included 20 selected septic shock patients, stratified on mHLA-DR expression, with samples collected on day 1 and day 3 after inclusion. We validated the results in an unselected, independent cohort that included 100 septic shock patients on day 3 after inclusion. We compared septic shock patients, according to their immune status, to describe the transcriptional HERV/MaLR and conventional gene expression. For differential expression analyses, moderated t tests were performed and Wilcoxon signed-rank tests were used to analyze RT-qPCR results. RESULTS: We showed that 6.9% of the HERV/MaLR repertoire was transcribed in the whole blood, and septic shock was associated with an early modulation of a few thousand of these loci, in comparison to healthy volunteers. We provided evidence that a subset of HERV/MaLR and conventional genes were differentially expressed in septic shock patients, according to their immune status, using monocyte HLA-DR (mHLA-DR) expression as a proxy. A group of 193 differentially expressed HERV/MaLR probesets, tested in an independent septic shock cohort, identified two groups of patients with different immune status and severity features. CONCLUSION: We demonstrated that a large, unexplored part of our genome, which codes for HERV/MaLR, may be linked to the host immune response. The identified set of HERV/MaLR probesets should be evaluated on a large scale to assess the relevance of these loci in the stratification of septic shock patients. This may help to address the heterogeneity of these patients.


Assuntos
Retrovirus Endógenos/genética , Choque Séptico , Transcriptoma/genética , Idoso , Feminino , Antígenos HLA-DR , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Projetos Piloto , Retroelementos , Choque Séptico/sangue , Choque Séptico/genética , Choque Séptico/imunologia , Sequências Repetidas Terminais
15.
Proc Natl Acad Sci U S A ; 117(14): 7905-7916, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32193341

RESUMO

Transposable elements (TEs) compose nearly half of mammalian genomes and provide building blocks for cis-regulatory elements. Using high-throughput sequencing, we show that 84 TE subfamilies are overrepresented, and distributed in a lineage-specific fashion in core and boundary domains of CD8+ T cell enhancers. Endogenous retroviruses are most significantly enriched in core domains with accessible chromatin, and bear recognition motifs for immune-related transcription factors. In contrast, short interspersed elements (SINEs) are preferentially overrepresented in nucleosome-containing boundaries. A substantial proportion of these SINEs harbor a high density of the enhancer-specific histone mark H3K4me1 and carry sequences that match enhancer boundary nucleotide composition. Motifs with regulatory features are better preserved within enhancer-enriched TE copies compared to their subfamily equivalents located in gene deserts. TE-rich and TE-poor enhancers associate with both shared and unique gene groups and are enriched in overlapping functions related to lymphocyte and leukocyte biology. The majority of T cell enhancers are shared with other immune lineages and are accessible in common hematopoietic progenitors. A higher proportion of immune tissue-specific enhancers are TE-rich compared to enhancers specific to other tissues, correlating with higher TE occurrence in immune gene-associated genomic regions. Our results suggest that during evolution, TEs abundant in these regions and carrying motifs potentially beneficial for enhancer architecture and immune functions were particularly frequently incorporated by evolving enhancers. Their putative selection and regulatory cooption may have accelerated the evolution of immune regulatory networks.


Assuntos
Elementos de DNA Transponíveis/genética , Elementos Facilitadores Genéticos/genética , Evolução Molecular , Linfócitos T/imunologia , Animais , Cromatina/genética , Cromatina/imunologia , Elementos de DNA Transponíveis/imunologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Elementos Facilitadores Genéticos/imunologia , Redes Reguladoras de Genes/genética , Genoma Humano/genética , Genoma Humano/imunologia , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Elementos Nucleotídeos Curtos e Dispersos/genética , Elementos Nucleotídeos Curtos e Dispersos/imunologia
16.
APMIS ; 128(5): 367-377, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32202683

RESUMO

Human endogenous retroviruses (HERV)-E consist of a family of more than 1300 elements, stably integrated in the human genome. Some of them are full-length proviruses able to synthesize the viral proteins gag, pol and env. The reactivation of HERV-E elements has been associated to placentation, cancer and autoimmunity. In this narrative review, we aimed to report the status of the art concerning the involvement of HERV-E in rheumatic autoimmune diseases. Following a research on PubMed database, a total of 87 articles were selected. The highest amount of evidence derives from studies on systemic lupus erythematosus (SLE), whereas a few to no data are available on other immune-mediated diseases. In SLE, the hyper-expression of HERV-E clone 4-1 in peripheral blood mononuclear cells or differentiated lymphocytes has been associated with disease activity and autoantibody production. It is likely that HERV-E take part to the pathogenesis of rheumatic autoimmune diseases but additional research is needed.


Assuntos
Retrovirus Endógenos/genética , Leucócitos Mononucleares/virologia , Lúpus Eritematoso Sistêmico/genética , Doenças Reumáticas/genética , Metilação de DNA , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/virologia , Doenças Reumáticas/imunologia , Doenças Reumáticas/virologia
17.
Virology ; 544: 21-30, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32174511

RESUMO

Human endogenous retroviruses (HERVs), the remains of retroviruses infection in our ancestors' germline cell over millions of years, take up about 8% of the human genome in total. HERV transcription has been detected in various cancers and diseases. However, the interaction between HERV expression and viral infection has not been fully elucidated. Here, we provided the first transcriptional profile of HERVs in dengue virus serotype 2 (DENV-2) infected A549 cells by using high-throughput RNA sequencing. The results showed that a number of HERVs and human genes were significantly differentially expressed in response to DENV-2 infection. Further bioinformatic analyses indicated a correlation between HERVs and human genes. In particular, the genes near the HERVs activated by dengue infection were dominantly enriched in the antiviral immune response. Taken together, our findings suggest that activated HERVs may be involved in the cellular immune response to viral infection by coexpressing with nearby host genes.


Assuntos
Vírus da Dengue/fisiologia , Retrovirus Endógenos/metabolismo , Ativação Transcricional , Células A549 , Vírus da Dengue/genética , Retrovirus Endógenos/genética , Regulação Viral da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Sorogrupo
18.
Radiat Res ; 193(4): 305-317, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32074012

RESUMO

The generation of DNA double-strand breaks has historically been taught as the mechanism through which radiotherapy kills cancer cells. Recently, radiation-induced cytosolic DNA release and activation of the cGAS/STING pathway, with ensuing induction of interferon secretion and immune activation, have been recognized as important mechanisms for radiation-mediated anti-tumor efficacy. Here we demonstrate that radiation-induced activation of endogenous retroviruses (ERVs) also plays a major role in regulating the anti-tumor immune response during irradiation. Radiation-induced ERV-associated dsRNA transcription and subsequent activation of the innate antiviral MDA5/MAVS/TBK1 pathway led to downstream transcription of interferon-stimulated genes. Additionally, genetic knockout of KAP1, a chromatin modulator responsible for suppressing ERV transcription sites within the genome, enhanced the effect of radiation-induced anti-tumor response in vivo in two different tumor models. This anti-tumor response was immune-mediated and required an intact host immune system. Our findings indicate that radiation-induced ERV-dsRNA expression and subsequent immune response play critical roles in clinical radiotherapy, and manipulation of epigenetic regulators and the dsRNA-sensing innate immunity pathway could be promising targets to enhance the efficacy of radiotherapy and cancer immunotherapy.


Assuntos
Quebras de DNA de Cadeia Dupla/efeitos da radiação , Imunidade Inata/imunologia , Neoplasias/imunologia , Neoplasias/radioterapia , Células A549 , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Retrovirus Endógenos/genética , Retrovirus Endógenos/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Técnicas de Inativação de Genes , Humanos , Imunidade Inata/efeitos da radiação , Imunoterapia/métodos , Helicase IFIH1 Induzida por Interferon/genética , Camundongos , Neoplasias/genética , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos da radiação , Proteína 28 com Motivo Tripartido/genética , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Eur J Immunol ; 50(5): 685-694, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32012247

RESUMO

Syncytin-1 is the envelope protein of the human endogenous retrovirus W (HERV-W). It has been related to multiple sclerosis (MS) but its role in cellular immunity and its pathogenic mechanism in the autoimmune context are not fully understood. We analyzed syncytin-1 levels in peripheral blood mononuclear cells (PBMC) subsets from healthy donors, MS patients in relapse or remission, and patients with acute infections by flow cytometry. PBMC cultures were also prepared to analyze protein expression kinetics. MS patients had higher levels of syncytin-1 levels than controls. We found that syncytin-1 is elevated in monocytes during MS relapses and infections. Cells expressing syncytin-1, including monocytes, T and B lymphocytes, and NKs presented mainly an activated phenotype and, upon stimulation with LPS, its levels increased rapidly on antigen-presenting cells. Syncytin-1 ligation promoted the activation of monocytes, as demonstrated by the upregulation of CD80 and the nonclassical subset CD14low CD16+ . Our results suggest an important role for syncytin-1 in the activation of leukocytes. Given that the expression of syncytin-1 is upregulated in MS patients, this protein might be contributing to the autoimmune cascade in the disease.


Assuntos
Retrovirus Endógenos/imunologia , Produtos do Gene env/genética , Monócitos/virologia , Esclerose Múltipla/genética , Esclerose Múltipla/virologia , Proteínas da Gravidez/genética , Adulto , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/virologia , Antígeno B7-1/genética , Antígeno B7-1/imunologia , Estudos de Casos e Controles , Retrovirus Endógenos/genética , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Regulação da Expressão Gênica , Produtos do Gene env/imunologia , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/virologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Proteínas da Gravidez/imunologia , Cultura Primária de Células , Receptores de IgG/genética , Receptores de IgG/imunologia , Recidiva , Indução de Remissão , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/virologia
20.
BMC Musculoskelet Disord ; 21(1): 27, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937280

RESUMO

BACKGROUND: There is some limited evidence for the presence of viruses in herniated disc material including a previous case series that claimed to provide "unequivocal evidence of the presence of herpes virus DNA in intervertebral disc specimens of patients with lumbar disc herniation suggesting the potential role of herpes viruses as a contributing factor to the pathogenesis of degenerative disc disease". This study has not been replicated. The objective of our study was to determine if viruses were present in herniated disc fragments in participants with a prior history of back pain. METHODS: We recruited fifteen participants with a history of prior low-back pain prior to undergoing disc herniation surgery in the lumbar spine. Harvested disc samples were subject to next generation sequencing for detection of both RNA and DNA viral pathogens. Additionally, samples were analysed by a broadly reactive PCR targeting herpesviral DNA. Ethics approval was granted by the Human Research Ethics Committees of both Murdoch University, and St John of God Hospital, Western Australia. RESULTS: Of the fifteen research participants, 8 were female. Mean age was 49.4 years (SD 14.5 yrs) with a range of 24-70 years. All participants had prior back pain with mean time since first ever attack being 8.8 years (SD 8.8 yrs). No samples contained significant DNA sequences relating to known human viral agents. Inconsequential retroviral sequences were commonly found and were a mixture of putative animal and human retroviral protein coding segments. All samples were negative for herpesvirus DNA when analysed by pan-herpesvirus PCR. CONCLUSIONS: This study found no viral pathogens in any intervertebral disc fragments of patients who had previous back pain and underwent discectomy for disc herniation and thus it is unlikely that viruses are associated with disc herniation, however given the contradiction between key studies enhanced replication of this experiment is recommended.


Assuntos
DNA Viral/isolamento & purificação , Deslocamento do Disco Intervertebral/virologia , Disco Intervertebral/virologia , Vértebras Lombares/virologia , Adulto , Idoso , Discotomia , Retrovirus Endógenos/genética , Retrovirus Endógenos/isolamento & purificação , Feminino , Herpesviridae/genética , Herpesviridae/isolamento & purificação , Humanos , Deslocamento do Disco Intervertebral/cirurgia , Masculino , Pessoa de Meia-Idade , RNA Viral/isolamento & purificação , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...