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1.
J Mol Biol ; : 167247, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34537236

RESUMO

Signaling initiated by type I interferon (IFN) results in the induction of hundreds of IFN-stimulated genes (ISGs). The type I IFN response is important for antiviral restriction, but aberrant activation of this response can lead to inflammation and autoimmunity. Regulation of this response is incompletely understood. We previously reported that the mRNA modification m6A and its deposition enzymes, METTL3 and METTL14 (METTL3/14), promote the type I IFN response by directly modifying the mRNA of a subset of ISGs to enhance their translation. Here, we determined the role of the RNA demethylase fat mass and obesity-associated protein (FTO) in the type I IFN response. FTO, which can remove either m6A or cap-adjacent m6Am RNA modifications, has previously been associated with obesity and body mass index, type 2 diabetes, cardiovascular disease, and inflammation. We found that FTO suppresses the transcription of a distinct set of ISGs, including many known pro-inflammatory genes, and that this regulation requires its catalytic activity but is not through the actions of FTO on m6Am. Interestingly, depletion of FTO led to activation of the transcription factor STAT3, whose role in the type I IFN response is not well understood. This activation of STAT3 increased the expression of a subset of ISGs. Importantly, this increased ISG induction resulting from FTO depletion was partially ablated by depletion of STAT3. Together, these results reveal that FTO negatively regulates STAT3-mediated signaling that induces proinflammatory ISGs during the IFN response, highlighting an important role for FTO in suppression of inflammatory genes.

2.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34342578

RESUMO

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.


Assuntos
2',5'-Oligoadenilato Sintetase/metabolismo , COVID-19/virologia , SARS-CoV-2/metabolismo , Animais , COVID-19/imunologia , Sistemas CRISPR-Cas , Linhagem Celular , Edição de Genes , Humanos , Polimorfismo de Nucleotídeo Único , SARS-CoV-2/isolamento & purificação
3.
Immunol Rev ; 304(1): 77-96, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34405416

RESUMO

From the initial sensing of viral nucleotides by pattern recognition receptors, through the induction of type I and III interferons (IFN), upregulation of antiviral effector proteins, and resolution of the inflammatory response, each step of innate immune signaling is under tight control. Though innate immunity is often associated with broad regulation at the level of gene transcription, RNA-centric post-transcriptional processes have emerged as critical mechanisms for ensuring a proper antiviral response. Here, we explore the diverse RNA regulatory mechanisms that modulate the innate antiviral immune response, with a focus on RNA sensing by RIG-I-like receptors (RLR), interferon (IFN) and IFN signaling pathways, viral pathogenesis, and host genetic variation that contributes to these processes. We address the post-transcriptional interactions with RNA-binding proteins, non-coding RNAs, transcript elements, and modifications that control mRNA stability, as well as alternative splicing events that modulate the innate immune antiviral response.

4.
Sci Immunol ; 6(61)2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215679

RESUMO

Excessive cytokine activity underlies many autoimmune conditions, particularly through the interleukin-17 (IL-17) and tumor necrosis factor-α (TNFα) signaling axis. Both cytokines activate nuclear factor κB, but appropriate induction of downstream effector genes requires coordinated activation of other transcription factors, notably, CCAAT/enhancer binding proteins (C/EBPs). Here, we demonstrate the unexpected involvement of a posttranscriptional "epitranscriptomic" mRNA modification [N6-methyladenosine (m6A)] in regulating C/EBPß and C/EBPδ in response to IL-17A, as well as IL-17F and TNFα. Prompted by the observation that C/EBPß/δ-encoding transcripts contain m6A consensus sites, we show that Cebpd and Cebpb mRNAs are subject to m6A modification. Induction of C/EBPs is enhanced by an m6A methylase "writer" and suppressed by a demethylase "eraser." The only m6A "reader" found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of Cebpd and Cebpb mRNA was enhanced by m6A modification. IMP2 facilitated IL-17-mediated Cebpd mRNA stabilization and promoted translation of C/EBPß/δ in response to IL-17A, IL-17F, and TNFα. RNA sequencing revealed transcriptome-wide IL-17-induced transcripts that are IMP2 influenced, and RNA immunoprecipitation sequencing identified the subset of mRNAs that are directly occupied by IMP2, which included Cebpb and Cebpd Lipocalin-2 (Lcn2), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBPß/δ. Imp2-/- mice were resistant to autoantibody-induced glomerulonephritis (AGN), showing impaired renal expression of C/EBPs and Lcn2 Moreover, IMP2 deletion initiated only after AGN onset ameliorated disease. Thus, posttranscriptional regulation of C/EBPs through m6A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation.

5.
Cell Rep ; 34(9): 108798, 2021 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-33657363

RESUMO

Type I interferons (IFNs) induce hundreds of IFN-stimulated genes (ISGs) in response to viral infection. Induction of these ISGs must be regulated for an efficient and controlled antiviral response, but post-transcriptional controls of these genes have not been well defined. Here, we identify a role for the RNA base modification N6-methyladenosine (m6A) in the regulation of ISGs. Using ribosome profiling and quantitative mass spectrometry, coupled with m6A-immunoprecipitation and sequencing, we identify a subset of ISGs, including IFITM1, whose translation is enhanced by m6A and the m6A methyltransferase proteins METTL3 and METTL14. We further determine that the m6A reader YTHDF1 increases the expression of IFITM1 in an m6A-binding-dependent manner. Importantly, we find that the m6A methyltransferase complex promotes the antiviral activity of type I IFN. Thus, these studies identify m6A as having a role in post-transcriptional control of ISG translation during the type I IFN response for antiviral restriction.

6.
Cell ; 183(5): 1185-1201.e20, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33242417

RESUMO

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.


Assuntos
Genômica , Mitocôndrias/patologia , Voo Espacial , Estresse Fisiológico , Animais , Ritmo Circadiano , Matriz Extracelular/metabolismo , Humanos , Imunidade Inata , Metabolismo dos Lipídeos , Análise do Fluxo Metabólico , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Músculos/imunologia , Especificidade de Órgãos , Olfato/fisiologia
7.
Nat Commun ; 11(1): 6016, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243990

RESUMO

Adenovirus is a nuclear replicating DNA virus reliant on host RNA processing machinery. Processing and metabolism of cellular RNAs can be regulated by METTL3, which catalyzes the addition of N6-methyladenosine (m6A) to mRNAs. While m6A-modified adenoviral RNAs have been previously detected, the location and function of this mark within the infectious cycle is unknown. Since the complex adenovirus transcriptome includes overlapping spliced units that would impede accurate m6A mapping using short-read sequencing, here we profile m6A within the adenovirus transcriptome using a combination of meRIP-seq and direct RNA long-read sequencing to yield both nucleotide and transcript-resolved m6A detection. Although both early and late viral transcripts contain m6A, depletion of m6A writer METTL3 specifically impacts viral late transcripts by reducing their splicing efficiency. These data showcase a new technique for m6A discovery within individual transcripts at nucleotide resolution, and highlight the role of m6A in regulating splicing of a viral pathogen.


Assuntos
Adenosina/análogos & derivados , Infecções por Adenovirus Humanos/virologia , Adenovírus Humanos/genética , Splicing de RNA , RNA Viral/metabolismo , Células A549 , Adenosina/metabolismo , Adenovírus Humanos/patogenicidade , DNA Viral/genética , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Células HEK293 , Interações Hospedeiro-Patógeno/genética , Humanos , Metiltransferases/genética , Metiltransferases/metabolismo , RNA Interferente Pequeno/metabolismo , RNA Viral/genética , Análise de Sequência de RNA , Replicação Viral
8.
mSphere ; 5(3)2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32404510

RESUMO

Type I interferons (IFN) initiate an antiviral state through a signal transduction cascade that leads to the induction of hundreds of IFN-stimulated genes (ISGs) to restrict viral infection. Recently, RNA modifications on both host and viral RNAs have been described as regulators of infection. However, the impact of host mRNA cap modifications on the IFN response and how this regulates viral infection are unknown. Here, we reveal that CMTR1, an ISG that catalyzes 2'-O-methylation of the first transcribed nucleotide in cellular mRNA (Cap 1), promotes the protein expression of specific ISGs that contribute to the antiviral response. Depletion of CMTR1 reduces the IFN-induced protein levels of ISG15, MX1, and IFITM1, without affecting their transcript abundance. However, CMTR1 depletion does not significantly affect the IFN-induced protein or transcript abundance of IFIT1 and IFIT3. Importantly, knockdown of IFIT1, which acts with IFIT3 to inhibit the translation of RNAs lacking Cap 1 2'-O-methylation, restores protein expression of ISG15, MX1, and IFITM1 in cells depleted of CMTR1. Finally, we found that CMTR1 plays a role in restricting RNA virus replication, likely by ensuring the expression of specific antiviral ISGs. Taken together, these data reveal that CMTR1 is required to establish an antiviral state by ensuring the protein expression of a subset of ISGs during the type I IFN response.IMPORTANCE Induction of an efficient type I IFN response is important to control viral infection. We show that the host 2'-O-methyltransferase CMTR1 facilitates the protein expression of ISGs in human cells by preventing IFIT1 from inhibiting the translation of those mRNAs lacking cap 2'-O-methylation. Thus, CMTR1 promotes the IFN-mediated antiviral response.


Assuntos
Regulação da Expressão Gênica/imunologia , Interferon Tipo I/imunologia , Metiltransferases/genética , RNA Mensageiro/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Linhagem Celular , Células HEK293 , Humanos , Imunidade Inata , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metilação , Biossíntese de Proteínas , Vírus de RNA/imunologia , Vírus de RNA/fisiologia , Proteínas de Ligação a RNA/genética , Transdução de Sinais , Células THP-1 , Replicação Viral/imunologia
9.
Sci Rep ; 10(1): 6590, 2020 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-32313079

RESUMO

Many cellular mRNAs contain the modified base m6A, and recent studies have suggested that various stimuli can lead to changes in m6A. The most common method to map m6A and to predict changes in m6A between conditions is methylated RNA immunoprecipitation sequencing (MeRIP-seq), through which methylated regions are detected as peaks in transcript coverage from immunoprecipitated RNA relative to input RNA. Here, we generated replicate controls and reanalyzed published MeRIP-seq data to estimate reproducibility across experiments. We found that m6A peak overlap in mRNAs varies from ~30 to 60% between studies, even in the same cell type. We then assessed statistical methods to detect changes in m6A peaks as distinct from changes in gene expression. However, from these published data sets, we detected few changes under most conditions and were unable to detect consistent changes across studies of similar stimuli. Overall, our work identifies limits to MeRIP-seq reproducibility in the detection both of peaks and of peak changes and proposes improved approaches for analysis of peak changes.


Assuntos
Adenosina/genética , RNA Mensageiro/isolamento & purificação , RNA/isolamento & purificação , Algoritmos , Sequência de Bases , Humanos , Imunoprecipitação , Metilação , RNA/genética , RNA Mensageiro/genética , Análise de Sequência de RNA , Software
10.
Mol Cell ; 77(3): 542-555.e8, 2020 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-31810760

RESUMO

The RNA modification N6-methyladenosine (m6A) modulates mRNA fate and thus affects many biological processes. We analyzed m6A across the transcriptome following infection by dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and hepatitis C virus (HCV). We found that infection by these viruses in the Flaviviridae family alters m6A modification of specific cellular transcripts, including RIOK3 and CIRBP. During viral infection, the addition of m6A to RIOK3 promotes its translation, while loss of m6A in CIRBP promotes alternative splicing. Importantly, viral activation of innate immune sensing or the endoplasmic reticulum (ER) stress response contributes to the changes in m6A in RIOK3 or CIRBP, respectively. Further, several transcripts with infection-altered m6A profiles, including RIOK3 and CIRBP, encode proteins that influence DENV, ZIKV, and HCV infection. Overall, this work reveals that cellular signaling pathways activated during viral infection lead to alterations in m6A modification of host mRNAs to regulate infection.


Assuntos
Adenosina/análogos & derivados , Infecções por Flaviviridae/genética , RNA Mensageiro/genética , Adenosina/genética , Linhagem Celular , Dengue/virologia , Vírus da Dengue/genética , Flaviviridae/genética , Hepacivirus/genética , Hepatite C/virologia , Interações Hospedeiro-Patógeno/genética , Humanos , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Replicação Viral/genética , Zika virus/genética , Infecção por Zika virus/genética
11.
Annu Rev Virol ; 6(1): 235-253, 2019 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-31283446

RESUMO

In recent years, the RNA modification N6-methyladenosine (m6A) has been found to play a role in the life cycles of numerous viruses and also in the cellular response to viral infection. m6A has emerged as a regulator of many fundamental aspects of RNA biology. Here, we highlight recent advances in techniques for the study of m6A, as well as advances in our understanding of the cellular machinery that controls the addition, removal, recognition, and functions of m6A. We then summarize the many newly discovered roles of m6A during viral infection, including how it regulates innate and adaptive immune responses to infection. Overall, the goals of this review are to summarize the roles of m6A on both cellular and viral RNAs and to describe future directions for uncovering new functions of m6A during infection.


Assuntos
Adenosina/análogos & derivados , Regulação da Expressão Gênica , Interações entre Hospedeiro e Microrganismos , RNA Viral/química , Imunidade Adaptativa , Adenosina/química , Animais , Humanos , Imunidade Inata , Camundongos , Processamento Pós-Transcricional do RNA , RNA Viral/genética , Viroses/imunologia , Replicação Viral
12.
Proc Natl Acad Sci U S A ; 115(45): 11513-11518, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30341219

RESUMO

RNA virus genomes are efficient and compact carriers of biological information, encoding information required for replication both in their primary sequences and in higher-order RNA structures. However, the ubiquity of RNA elements with higher-order folds-in which helices pack together to form complex 3D structures-and the extent to which these elements affect viral fitness are largely unknown. Here we used single-molecule correlated chemical probing to define secondary and tertiary structures across the RNA genome of dengue virus serotype 2 (DENV2). Higher-order RNA structures are pervasive and involve more than one-third of nucleotides in the DENV2 genomic RNA. These 3D structures promote a compact overall architecture and contribute to viral fitness. Disrupting RNA regions with higher-order structures leads to stable, nonreverting mutants and could guide the development of vaccines based on attenuated RNA viruses. The existence of extensive regions of functional RNA elements with tertiary folds in viral RNAs, and likely many other messenger and noncoding RNAs, means that there are significant regions with pocket-containing surfaces that may serve as novel RNA-directed drug targets.


Assuntos
Capsídeo/ultraestrutura , Vírus da Dengue/ultraestrutura , Genoma Viral , RNA Viral/ultraestrutura , Pareamento de Bases , Capsídeo/química , Capsídeo/metabolismo , Vírus da Dengue/classificação , Vírus da Dengue/genética , Vírus da Dengue/metabolismo , Aptidão Genética , Modelos Moleculares , Conformação de Ácido Nucleico , RNA Viral/genética , RNA Viral/metabolismo , Sorogrupo , Montagem de Vírus/genética
13.
Proc Natl Acad Sci U S A ; 115(35): 8829-8834, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30104368

RESUMO

N6-methyladenosine (m6A) RNA methylation is the most abundant epitranscriptomic modification of eukaryotic messenger RNAs (mRNAs). Previous reports have found m6A on both cellular and viral transcripts and defined its role in regulating numerous biological processes, including viral infection. Here, we show that m6A and its associated machinery regulate the life cycle of hepatitis B virus (HBV). HBV is a DNA virus that completes its life cycle via an RNA intermediate, termed pregenomic RNA (pgRNA). Silencing of enzymes that catalyze the addition of m6A to RNA resulted in increased HBV protein expression, but overall reduced reverse transcription of the pgRNA. We mapped the m6A site in the HBV RNA and found that a conserved m6A consensus motif situated within the epsilon stem loop structure, is the site for m6A modification. The epsilon stem loop is located in the 3' terminus of all HBV mRNAs and at both the 5' and 3' termini of the pgRNA. Mutational analysis of the identified m6A site in the 5' epsilon stem loop of pgRNA revealed that m6A at this site is required for efficient reverse transcription of pgRNA, while m6A methylation of the 3' epsilon stem loop results in destabilization of all HBV transcripts, suggesting that m6A has dual regulatory function for HBV RNA. Overall, this study reveals molecular insights into how m6A regulates HBV gene expression and reverse transcription, leading to an increased level of understanding of the HBV life cycle.


Assuntos
Adenosina/análogos & derivados , Regulação Viral da Expressão Gênica/fisiologia , Vírus da Hepatite B/fisiologia , Conformação de Ácido Nucleico , Estabilidade de RNA , RNA Viral/biossíntese , Adenosina/genética , Adenosina/metabolismo , Células Hep G2 , Humanos , RNA Viral/genética , Transcrição Reversa/fisiologia , Proteínas Virais/biossíntese , Proteínas Virais/genética
16.
Cell Host Microbe ; 21(1): 1-2, 2017 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-28081439

RESUMO

In a recent issue of Science, Akiyama et al. (2016) prove the existence of a pseudoknot that stabilizes a nuclease-resistant RNA structure in the 3' untranslated region of Zika virus. This reinforced structure blocks the 5'→3' exonuclease Xrn1 for the production of pathogenic subgenomic flaviviral RNAs.


Assuntos
Exorribonucleases/metabolismo , Conformação de Ácido Nucleico , Estabilidade de RNA/genética , RNA Viral/genética , Zika virus/genética , Interações Hospedeiro-Patógeno , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologia
17.
Curr Opin Virol ; 22: 36-43, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27951430

RESUMO

The ability to recognize invading viral pathogens and to distinguish their components from those of the host cell is critical to initiate the innate immune response. The efficiency of this detection is an important factor in determining the susceptibility of the cell to viral infection. Innate sensing of viruses is, therefore, an indispensable step in the line of defense for cells and organisms. Recent discoveries have uncovered novel sensors of viral components and hallmarks of infection, as well as mechanisms by which cells discriminate between self and non-self. This review highlights the mechanisms used by cells to detect viral pathogens in the cytosol, and recent advances in the field of cytosolic sensing of viruses.


Assuntos
Citosol/imunologia , Citosol/virologia , Imunidade Inata , Receptores Imunológicos/metabolismo , Vírus/imunologia , Animais , Humanos
18.
Cell Host Microbe ; 20(5): 654-665, 2016 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-27773535

RESUMO

The RNA modification N6-methyladenosine (m6A) post-transcriptionally regulates RNA function. The cellular machinery that controls m6A includes methyltransferases and demethylases that add or remove this modification, as well as m6A-binding YTHDF proteins that promote the translation or degradation of m6A-modified mRNA. We demonstrate that m6A modulates infection by hepatitis C virus (HCV). Depletion of m6A methyltransferases or an m6A demethylase, respectively, increases or decreases infectious HCV particle production. During HCV infection, YTHDF proteins relocalize to lipid droplets, sites of viral assembly, and their depletion increases infectious viral particles. We further mapped m6A sites across the HCV genome and determined that inactivating m6A in one viral genomic region increases viral titer without affecting RNA replication. Additional mapping of m6A on the RNA genomes of other Flaviviridae, including dengue, Zika, yellow fever, and West Nile virus, identifies conserved regions modified by m6A. Altogether, this work identifies m6A as a conserved regulatory mark across Flaviviridae genomes.


Assuntos
Adenosina/análogos & derivados , Flaviviridae/genética , Flaviviridae/fisiologia , Regulação Viral da Expressão Gênica , Interações Hospedeiro-Patógeno , RNA Viral/metabolismo , Replicação Viral , Adenosina/metabolismo , Metiltransferases/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Carga Viral
19.
Cell Host Microbe ; 19(5): 675-85, 2016 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-27117054

RESUMO

Covalent addition of a methyl group to adenosine N(6) (m(6)A) is an evolutionarily conserved and common RNA modification that is thought to modulate several aspects of RNA metabolism. While the presence of multiple m(6)A editing sites on diverse viral RNAs was reported starting almost 40 years ago, how m(6)A editing affects virus replication has remained unclear. Here, we used photo-crosslinking-assisted m(6)A sequencing techniques to precisely map several m(6)A editing sites on the HIV-1 genome and report that they cluster in the HIV-1 3' untranslated region (3' UTR). Viral 3' UTR m(6)A sites or analogous cellular m(6)A sites strongly enhanced mRNA expression in cis by recruiting the cellular YTHDF m(6)A "reader" proteins. Reducing YTHDF expression inhibited, while YTHDF overexpression enhanced, HIV-1 protein and RNA expression, and virus replication in CD4+ T cells. These data identify m(6)A editing and the resultant recruitment of YTHDF proteins as major positive regulators of HIV-1 mRNA expression.


Assuntos
HIV-1/genética , HIV-1/metabolismo , Edição de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Regiões 3' não Traduzidas , Linfócitos T CD4-Positivos/virologia , Linhagem Celular , Clonagem Molecular , Regulação Viral da Expressão Gênica , Genoma Viral , Células HEK293 , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Humanos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Replicação Viral/efeitos dos fármacos
20.
J Leukoc Biol ; 96(3): 473-80, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24935957

RESUMO

Systemic inflammation that occurs with increasing age (inflammaging) is thought to contribute to the increased susceptibility of the elderly to several disease states. The elderly are at significant risk for developing pulmonary disorders and infectious diseases, but the contribution of inflammation in the pulmonary environment has received little attention. In this study, we demonstrate that the lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages that are refractory to further activation by IFN-γ. The impact of this inflammatory state on macrophage function was determined in vitro in response to infection with M.tb. Macrophages from the lungs of old mice secreted more proinflammatory cytokines in response to M.tb infection than similar cells from young mice and also demonstrated enhanced M.tb uptake and P-L fusion. Supplementation of mouse chow with the NSAID ibuprofen led to a reversal of lung and macrophage inflammatory signatures. These data indicate that the pulmonary environment becomes inflammatory with increasing age and that this inflammatory environment can be reversed with ibuprofen.


Assuntos
Envelhecimento/imunologia , Citocinas/biossíntese , Inflamação/imunologia , Pulmão/patologia , Macrófagos Alveolares/imunologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Genes Reporter , Ibuprofeno/farmacologia , Ibuprofeno/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/patologia , Interferon gama/farmacologia , Pulmão/crescimento & desenvolvimento , Pulmão/imunologia , Ativação de Macrófagos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/microbiologia , Fusão de Membrana , Camundongos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Fagossomos/fisiologia , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Recombinantes/farmacologia , Organismos Livres de Patógenos Específicos
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