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1.
MBio ; 10(3)2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113891

RESUMO

Mycofactocin (MFT) belongs to the class of ribosomally synthesized and posttranslationally modified peptides conserved in many Actinobacteria Mycobacterium tuberculosis assimilates cholesterol during chronic infection, and its in vitro growth in the presence of cholesterol requires most of the MFT biosynthesis genes (mftA, mftB, mftC, mftD, mftE, and mftF), although the reasons for this requirement remain unclear. To identify the function of MFT, we characterized MFT biosynthesis mutants constructed in Mycobacterium smegmatis, M. marinum, and M. tuberculosis We found that the growth deficit of mft deletion mutants in medium containing cholesterol-a phenotypic basis for gene essentiality prediction-depends on ethanol, a solvent used to solubilize cholesterol. Furthermore, functionality of MFT was strictly required for growth of free-living mycobacteria in ethanol and other primary alcohols. Among other genes encoding predicted MFT-associated dehydrogenases, MSMEG_6242 was indispensable for M. smegmatis ethanol assimilation, suggesting that it is a candidate catalytic interactor with MFT. Despite being a poor growth substrate, ethanol treatment resulted in a reductive cellular state with NADH accumulation in M. tuberculosis During ethanol treatment, mftC mutant expressed the transcriptional signatures that are characteristic of respirational dysfunction and a redox-imbalanced cellular state. Counterintuitively, there were no differences in cellular bioenergetics and redox parameters in mftC mutant cells treated with ethanol. Therefore, further understanding of the function of MFT in ethanol metabolism is required to identify the cause of growth retardation of MFT mutants in cholesterol. Nevertheless, our results establish the physiological role of MFT and also provide new insights into the specific functions of MFT homologs in other actinobacterial systems.IMPORTANCE Tuberculosis is caused by Mycobacterium tuberculosis, and the increasing emergence of multidrug-resistant strains renders current treatment options ineffective. Although new antimycobacterial drugs are urgently required, their successful development often relies on complete understanding of the metabolic pathways-e.g., cholesterol assimilation-that are critical for persistence and for pathogenesis of M. tuberculosis In this regard, mycofactocin (MFT) function appears to be important because its biosynthesis genes are predicted to be essential for M. tuberculosis in vitro growth in cholesterol. In determining the metabolic basis of this genetic requirement, our results unexpectedly revealed the essential function of MFT in ethanol metabolism. The metabolic dysfunction thereof was found to affect the mycobacterial growth in cholesterol which is solubilized by ethanol. This knowledge is fundamental in recognizing the bona fide function of MFT, which likely resembles the pyrroloquinoline quinone-dependent ethanol oxidation in acetic acid bacteria exploited for industrial production of vinegar.

2.
EMBO Rep ; 20(4)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30872316

RESUMO

Cyclic dinucleotides (CDNs) are important second messenger molecules in prokaryotes and eukaryotes. Within host cells, cytosolic CDNs are detected by STING and alert the host by activating innate immunity characterized by type I interferon (IFN) responses. Extracellular bacteria and dying cells can release CDNs, but sensing of extracellular CDNs (eCDNs) by mammalian cells remains elusive. Here, we report that endocytosis facilitates internalization of eCDNs. The DNA sensor cGAS facilitates sensing of endocytosed CDNs, their perinuclear accumulation, and subsequent STING-dependent release of type I IFN Internalized CDNs bind cGAS directly, leading to its dimerization, and the formation of a cGAS/STING complex, which may activate downstream signaling. Thus, eCDNs comprise microbe- and danger-associated molecular patterns that contribute to host-microbe crosstalk during health and disease.

3.
Proc Natl Acad Sci U S A ; 115(46): 11814-11819, 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30381461

RESUMO

mRNA decay plays an essential role in the control of gene expression in bacteria. Exoribonucleases (exoRNases), which trim transcripts starting from the 5' or 3' end, are particularly important to fully degrade unwanted transcripts and renew the pool of nucleotides available in the cell. While recent techniques have allowed genome-wide identification of ribonuclease (RNase) targets in bacteria in vivo, none of the 3'-to-5' exoRNase targetomes (i.e., global processing sites) have been studied so far. Here, we report the targetomes of YhaM, polynucleotide phosphorylase (PNPase), and RNase R of the human pathogen Streptococcus pyogenes We determined that YhaM is an unspecific enzyme that trims a few nucleotides and targets the majority of transcript ends, generated either by transcription termination or by endonucleolytic activity. The molecular determinants for YhaM-limited processivity are yet to be deciphered. We showed that PNPase clears the cell from mRNA decay fragments produced by endoribonucleases (endoRNases) and is the major 3'-to-5' exoRNase for RNA turnover in S. pyogenes In particular, PNPase is responsible for the degradation of regulatory elements from 5' untranslated regions. However, we observed little RNase R activity in standard culture conditions. Overall, our study sheds light on the very distinct features of S. pyogenes 3'-to-5' exoRNases.

4.
RNA Biol ; 15(10): 1336-1347, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30290721

RESUMO

Endoribonuclease Y (RNase Y) is a crucial regulator of virulence in Gram-positive bacteria. In the human pathogen Streptococcus pyogenes, RNase Y is required for the expression of the major secreted virulence factor streptococcal pyrogenic exotoxin B (SpeB), but the mechanism involved in this regulation remains elusive. Here, we demonstrate that the 5' untranslated region of speB mRNA is processed by several RNases including RNase Y. In particular, we identify two RNase Y cleavage sites located downstream of a guanosine (G) residue. To assess whether this nucleotide is required for RNase Y activity in vivo, we mutated it and demonstrate that the presence of this G residue is essential for the processing of the speB mRNA 5' UTR by RNase Y. Although RNase Y directly targets and processes speB, we show that RNase Y-mediated regulation of speB expression occurs primarily at the transcriptional level and independently of the processing in the speB mRNA 5' UTR. To conclude, we demonstrate for the first time that RNase Y processing of an mRNA target requires the presence of a G. We also provide new insights on the speB 5' UTR and on the role of RNase Y in speB regulation.

5.
Sci Rep ; 7(1): 12094, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28935874

RESUMO

Immunity in infection, inflammation and malignancy differs markedly in man and mouse. Still, we learn about human immunity in large extent from experimental mouse models. We propose a novel data integration approach which identifies concordant and discordant gene expression patterns of the immune responses in heterologous data sets. We have conducted experiments to compare human and murine transcriptional responses to Mycobacterium tuberculosis (Mtb) infection in whole blood (WB) as well as macrophages and compared them with simulated as well as publicly available data. Our results indicate profound differences between patterns of gene expression in innate and adaptive immunity in man and mouse upon Mtb infection. We characterized differential expression of T-cell related genes corresponding to the differences in phenotype between tuberculosis (TB) highly and low susceptible mouse strains. Our approach is general and facilitates the choice of optimal animal model for studies of the human immune response to a particular disease.

6.
Infect Immun ; 84(10): 2914-21, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27481246

RESUMO

The neonatal Fc receptor (FcRn) extends the systemic half-life of IgG antibodies by chaperoning bound Fc away from lysosomal degradation inside stromal and hematopoietic cells. FcRn also transports IgG across mucosal barriers into the lumen, and yet little is known about how FcRn modulates immunity in the lung during homeostasis or infection. We infected wild-type (WT) and FcRn-deficient (fcgrt(-/-)) mice with Pseudomonas aeruginosa or Mycobacterium tuberculosis to investigate whether recycling and transport of IgG via FcRn influences innate and adaptive immunity in the lung in response to bacterial infection. We found that FcRn expression maintains homeostatic IgG levels in lung and leads to preferential secretion of low-affinity IgG ligands into the lumen. Fcgrt(-/-) animals exhibited no evidence of developmental impairment of innate immunity in the lung and were able to efficiently recruit neutrophils in a model of acute bacterial pneumonia. Although local humoral immunity in lung increased independently of the presence of FcRn during tuberculosis, there was nonetheless a strong impact of FcRn deficiency on local adaptive immunity. We show that the quantity and quality of IgG in airways, as well as the abundance of dendritic cells in the lung, are maintained by FcRn. FcRn ablation transiently enhanced local T cell immunity and neutrophil recruitment during tuberculosis, leading to a lower bacterial burden in lung. This novel understanding of tissue-specific modulation of mucosal IgG isotypes in the lung by FcRn sheds light on the role of mucosal IgG in immune responses in the lung during homeostasis and bacterial disease.


Assuntos
Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe I/fisiologia , Imunoglobulina G/metabolismo , Pulmão , Receptores Fc/fisiologia , Tuberculose/imunologia , Imunidade Adaptativa , Animais , Antígenos CD/metabolismo , Carga Bacteriana , Células Dendríticas/citologia , Modelos Animais de Doenças , Antígenos de Histocompatibilidade Classe I/metabolismo , Imunidade Inata , Imunoglobulina G/imunologia , Cadeias alfa de Integrinas/metabolismo , Pulmão/citologia , Pulmão/imunologia , Pulmão/metabolismo , Camundongos , Camundongos Transgênicos , Membrana Mucosa/metabolismo , Mycobacterium tuberculosis , Células Mieloides/metabolismo , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa , Receptores Fc/metabolismo , Tuberculose/microbiologia
7.
Eur J Immunol ; 44(8): 2380-93, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24782112

RESUMO

General interest in the biological functions of IFN type I in Mycobacterium tuberculosis (Mtb) infection increased after the recent identification of a distinct IFN gene expression signature in tuberculosis (TB) patients. Here, we demonstrate that TB-susceptible mice lacking the receptor for IFN I (IFNAR1) were protected from death upon aerogenic infection with Mtb. Using this experimental model to mimic primary progressive pulmonary TB, we dissected the immune processes affected by IFN I. IFNAR1 signaling did not affect T-cell responses, but markedly altered migration of inflammatory monocytes and neutrophils to the lung. This process was orchestrated by IFNAR1 expressed on both immune and tissue-resident radioresistant cells. IFNAR1-driven TB susceptibility was initiated by augmented Mtb replication and in situ death events, along with CXCL5/CXCL1-driven accumulation of neutrophils in alveoli, followed by the discrete compartmentalization of Mtb in lung phagocytes. Early depletion of neutrophils rescued TB-susceptible mice to levels observed in mice lacking IFNAR1. We conclude that IFN I alters early innate events at the site of Mtb invasion leading to fatal immunopathology. These data furnish a mechanistic explanation for the detrimental role of IFN I in pulmonary TB and form a basis for understanding the complex roles of IFN I in chronic inflammation.


Assuntos
Interferon Tipo I/imunologia , Pulmão/imunologia , Fagócitos/imunologia , Transdução de Sinais/imunologia , Tuberculose Pulmonar/imunologia , Animais , Células Cultivadas , Quimiocina CXCL1/imunologia , Quimiocina CXCL5/imunologia , Inflamação/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Mycobacterium tuberculosis/imunologia , Neutrófilos/imunologia , Alvéolos Pulmonares/imunologia , Receptor de Interferon alfa e beta/imunologia , Linfócitos T/imunologia
8.
J Clin Invest ; 123(11): 4836-48, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24084739

RESUMO

The molecular mechanisms that control innate immune cell trafficking during chronic infection and inflammation, such as in tuberculosis (TB), are incompletely understood. During active TB, myeloid cells infiltrate the lung and sustain local inflammation. While the chemoattractants that orchestrate these processes are increasingly recognized, the posttranscriptional events that dictate their availability are unclear. We identified microRNA-223 (miR-223) as an upregulated small noncoding RNA in blood and lung parenchyma of TB patients and during murine TB. Deletion of miR-223 rendered TB-resistant mice highly susceptible to acute lung infection. The lethality of miR-223(­/­) mice was apparently not due to defects in antimycobacterial T cell responses. Exacerbated TB in miR-223(­/­) animals could be partially reversed by neutralization of CXCL2, CCL3, and IL-6, by mAb depletion of neutrophils, and by genetic deletion of Cxcr2. We found that miR-223 controlled lung recruitment of myeloid cells, and consequently, neutrophil-driven lethal inflammation. We conclude that miR-223 directly targets the chemoattractants CXCL2, CCL3, and IL-6 in myeloid cells. Our study not only reveals an essential role for a single miRNA in TB, it also identifies new targets for, and assigns biological functions to, miR-223. By regulating leukocyte chemotaxis via chemoattractants, miR-223 is critical for the control of TB and potentially other chronic inflammatory diseases.


Assuntos
MicroRNAs/genética , MicroRNAs/imunologia , Infiltração de Neutrófilos/genética , Tuberculose Pulmonar/genética , Animais , Quimiocina CCL3/metabolismo , Quimiocina CXCL2/metabolismo , Suscetibilidade a Doenças , Humanos , Imunidade Inata/genética , Interleucina-6/metabolismo , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/sangue , Infiltração de Neutrófilos/imunologia , Receptores de Interleucina-8B/deficiência , Receptores de Interleucina-8B/genética , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/patologia , Regulação para Cima
9.
Eur J Immunol ; 39(12): 3369-84, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19795415

RESUMO

Progression and outcome of tuberculosis is governed by extensive crosstalk between pathogen and host. Analyses of global changes in gene expression during immune response to infection with Mycobacterium tuberculosis (M.tb) can help identify molecular markers of disease state and progression. Global distribution of M.tb strains with different degrees of virulence and drug resistance, especially for the immunocompromised host, make closer analyses of host responses more pressing than ever. Here, we describe global transcriptional responses of inducible nitric oxide synthase-deficient (iNOS(-/-)) and WT mice infected with two related M.tb strains of markedly different virulence, namely the M.tb laboratory strains H37Rv and H37Ra. Both hosts exhibited highly similar resistance to infection with H37Ra. In contrast, iNOS(-/-) mice rapidly succumbed to H37Rv, whereas WT mice developed chronic course of disease. By differential analyses, virulence-specific changes in global host gene expression were analyzed to identify molecular markers characteristic for chronic versus acute infection. We identified several markers unique for different stages of disease progression and not previously associated with virulence-specific host responses in tuberculosis.


Assuntos
Perfilação da Expressão Gênica , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Animais , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Imunidade Inata/genética , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Mycobacterium tuberculosis/patogenicidade , Mycobacterium tuberculosis/fisiologia , Óxido Nítrico Sintase Tipo II/genética , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Fator de Crescimento Transformador beta1/genética , Tuberculose Pulmonar/microbiologia , Virulência
10.
Immunology ; 125(1): 38-47, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18298548

RESUMO

The intestinal mucosa represents a challenging environment for CD8+ T cells, which must tolerate nutrient antigens and commensal microorganisms while responding efficiently to pathogens. Consequently, specific regulatory mechanisms apply for CD8+ T cells in the intestinal environment, which should also be reflected in a tissue-specific gene expression profile of these cells. This study investigates whether such tissue-specific gene expression can be observed in CD8+ T cells primed during bacterial infection. To identify intestine-specific gene expression in conventional CD8alphabeta+ T cells, mice were infected with Listeria monocytogenes expressing ovalbumin (LmOVA). Using OVA257-264 tetramers, specific CD8+ T cells were sorted from spleen, liver and the small intestinal mucosa, and RNA samples from these cells were compared using microarrays. This approach allowed the identification of differences in gene expression in a highly defined CD8+ T-cell population with identical antigen specificity generated during infection. One group of genes with reduced expression in the intestinal mucosa comprised members of the C-type lectin-like natural killer receptor (NKR) family. Fluorescence-activated cell sorting analysis was used to assess protein expression of NKR. NKR expression on CD8+ T cells from the intestinal mucosa was dependent on the route of listeria application and consequently on the site of T-cell priming. Retinoic acid influenced NKR expression consistent with an imprinting of the NKR expression profile in intestine-associated lymphoid tissues. In contrast, NKR expression was largely independent from intestinal flora. Our results demonstrate that in the intestinal mucosa, conventional CD8alphabeta+ T cells lack NKR expression and thereby lose responsiveness to NKR ligands, which otherwise could possibly cause adverse activation or inhibition of T cells in this environment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Intestino Delgado/imunologia , Lectinas Tipo C/metabolismo , Listeriose/imunologia , Receptores KIR/metabolismo , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Células Cultivadas , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Vida Livre de Germes , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestino Delgado/microbiologia , Lectinas Tipo C/genética , Fígado/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Receptores KIR/genética , Baço/imunologia , Tretinoína/farmacologia
11.
Immunology ; 123(1): 45-56, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17916165

RESUMO

Natural killer T (NKT) cells constitute a distinct lymphocyte lineage at the interface between innate and adaptive immunity, yet their role in the immune response remains elusive. Whilst NKT cells share features with other conventional T lymphocytes, they are unique in their rapid, concomitant production of T helper type 1 (Th1) and Th2 cytokines upon T-cell receptor (TCR) ligation. In order to characterize the gene expression of NKT cells, we performed comparative microarray analyses of murine resting NKT cells, natural killer (NK) cells and naïve conventional CD4+ T helper (Th) and regulatory T cells (Treg). We then compared the gene expression profiles of resting and alpha-galactosylceramide (alphaGalCer)-activated NKT cells to elucidate the gene expression signature upon activation. We describe here profound differences in gene expression among the various cell types and the identification of a unique NKT cell gene expression profile. In addition to known NKT cell-specific markers, many genes were expressed in NKT cells that had not been attributed to this population before. NKT cells share features not only with Th1 and Th2 cells but also with Th17 cells. Our data provide new insights into the functional competence of NKT cells which will facilitate a better understanding of their versatile role during immune responses.


Assuntos
Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reação em Cadeia da Polimerase/métodos , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia
12.
J Biotechnol ; 128(1): 1-13, 2007 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-17084936

RESUMO

Microarrays have rapidly become an indispensable tool for gene analysis. Microarray experiments can be cost prohibitive, however, largely due to the price of the arrays themselves. Whilst different methods for stripping filter arrays on membranes have been established, only very few protocols are published for thermal and chemical stripping of microarrays on glass. Most of these protocols for stripping microarrays on glass were developed in combination with specific surface chemistry and different coatings for covalently immobilizing presynthesized DNA in a deposition process. We have developed a method for stripping commercial in situ microarrays using a multi-step procedure. We present a method that uses mild chemical degradation complemented by enzymatic treatment. We took advantage of the differences in biochemical properties of covalently linked DNA oligonucleotides on in situ synthesized microarrays and the antisense cRNA hybridization probes. The success of stripping protocols for microarrays on glass was critically dependent on the type of arrays, the nature of sample used for hybridization, as well as hybridization and washing conditions. The protocol employs alkali hydrolysis of the cRNA, several enzymatic degradation steps using RNAses and Proteinase K, combined with appropriate washing steps. Stripped arrays were rehybridized using the same protocols as for new microarrays. The stripping method was validated with microarrays from different suppliers and rehybridization of stripped in situ arrays yielded comparable results to hybridizations done on unused, new arrays with no significant loss in precision or accuracy. We show that stripping of commercial in situ arrays is feasible and that reuse of stripped arrays gave similar results compared to unused ones. This was true even for biological samples that show only slight differences in their expression profiles. Our analyses indicate that the stripping procedure does not significantly influence data quality derived from post-primary hybridizations. The method is robust, easy to perform, inexpensive, and results after reuse are of comparable accuracy to new arrays.


Assuntos
Perfilação da Expressão Gênica/instrumentação , Análise de Sequência com Séries de Oligonucleotídeos/instrumentação , Controle de Custos , Reutilização de Equipamento , Perfilação da Expressão Gênica/economia , Perfilação da Expressão Gênica/métodos , Vidro , Indicadores e Reagentes/economia , Análise de Sequência com Séries de Oligonucleotídeos/economia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Reprodutibilidade dos Testes
13.
Eur J Immunol ; 36(3): 631-47, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16479545

RESUMO

A potent Th1 immune response is critical to the control of tuberculosis. The impact of an additive Th2 response on the course of disease has so far been insufficiently characterized, despite increased morbidity after co-infection with Mycobacterium tuberculosis and Th2-eliciting helminths and possible involvement of Th2 polarization in reactivation of latent tuberculosis. Here, we describe the gene expression profile of murine bone marrow-derived macrophages alternatively activated by IL-4 in response to infection with M. tuberculosis. Comparison of transcriptional profiles of infected IL-4- and IFN-gamma-activated macrophages revealed delayed and partially diminished responses to intracellular bacteria in alternatively activated macrophages, characterized by reduced exposure to nitrosative stress and increased iron availability, respectively. Alternative activation of host macrophages correlated with elevated expression of the M. tuberculosis iron storage protein bacterioferritin as well as reduced expression of the mycobactin synthesis genes mbtI and mbtJ. The extracellular matrix-remodeling enzyme matrix metalloproteinase (MMP)-12 was induced in alternatively activated macrophages in vitro, and MMP-12-expressing macrophages were abundant at late, but not early, stages of tuberculosis in murine lungs. Our findings emphasize that alternative activation deprives macrophages of control mechanisms that limit mycobacterial growth in vivo, thus supporting intracellular persistence of M. tuberculosis.


Assuntos
Células da Medula Óssea/imunologia , Regulação da Expressão Gênica/imunologia , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/imunologia , Animais , Antineoplásicos/farmacologia , Proteínas de Bactérias/imunologia , Células da Medula Óssea/microbiologia , Células da Medula Óssea/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Regulação Bacteriana da Expressão Gênica/genética , Regulação Bacteriana da Expressão Gênica/imunologia , Helmintíase/imunologia , Helmintíase/patologia , Interferon gama/farmacologia , Interleucina-4/farmacologia , Ferro/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Macrófagos/patologia , Metaloproteinase 12 da Matriz , Metaloendopeptidases/imunologia , Camundongos , Mycobacterium tuberculosis/genética , Oxazóis/imunologia , Células Th1/imunologia , Células Th2/imunologia , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/patologia
14.
Microbes Infect ; 8(1): 136-44, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16257251

RESUMO

Transcriptome analyses enable the assessment of signature alterations in whole tissues and organs undergoing pathological processes. We analyzed gene expression profiles of lungs from mice infected with Mycobacterium tuberculosis or vaccinated with Mycobacterium bovis bacille Calmette-Guérin (BCG). We compared high-dose systemic and low-dose aerosol M. tuberculosis infections as well as systemic BCG vaccination. Expression profiles in lungs were analyzed at day (d) 1 and d 30 post infection / vaccination using a custom tailored 'in situ' synthesized 60-mer oligonucleotide microarray with focus on immunologically relevant genes. At d 1, a small number of genes were differentially regulated, whereas at d 30, a discrete expression pattern was identified in the lung. Differential gene expression profiles between M. tuberculosis infection and BCG vaccination indicate differences in naturally and vaccine induced pulmonary immune responses. The shared signature of systemic and aerosol M. tuberculosis infection revealed dominance of genes related to or controlled by interferon gamma (IFN-gamma). We assume that differential gene expression profiles after M. tuberculosis infection are strongly influenced by differences in cellular composition of the lung due to migration of immune cells, primarily neutrophils, basophils, eosinophils and monocytes to the site of infection.


Assuntos
Vacina BCG/imunologia , Perfilação da Expressão Gênica , Pulmão/imunologia , Pulmão/metabolismo , Mycobacterium tuberculosis/imunologia , Transcrição Genética , Tuberculose/prevenção & controle , Animais , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium tuberculosis/fisiologia , Tuberculose/imunologia , Tuberculose/microbiologia , Vacinação
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