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1.
Artigo em Inglês | MEDLINE | ID: mdl-34062980

RESUMO

Antibiotic pollution has become an increasingly serious issue due to the extensive application of antibiotics, their resistance to removal, and the harmful effects on aquatic environments and humans. Breeding wastewater is one of the most important sources of antibiotics in the aquatic environment because of the undeveloped treatment systems in breeding farms. It is imperative to establish an effective antibiotic removal process for breeding wastewater. This paper reviews the treatment methods used to remove antibiotics from breeding wastewater. The mechanisms and removal efficiency of constructed wetlands, biological treatments, advanced oxidation processes (AOPs), membrane technology, and combined treatments are explained in detail, and the advantages and disadvantages of the various treatment methods are compared and analyzed. Constructed wetlands have high removal rates for sulfonamide (SM), tetracycline (TC), and quinolone (QN). The antibiotic removal efficiency of biological treatment methods is affected by various processes and environmental factors, whereas AOPs and combined treatment methods have better antibiotic removal effects. Although it has broad application prospects, the application of membrane technology for the treatment of antibiotics in breeding wastewater needs further research.


Assuntos
Águas Residuárias , Poluentes Químicos da Água , Antibacterianos , Humanos , Eliminação de Resíduos Líquidos , Águas Residuárias/análise , Poluentes Químicos da Água/análise , Áreas Alagadas
2.
ACS Infect Dis ; 7(3): 672-680, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33650856

RESUMO

Antibiotic resistance is a daunting challenge in modern medicine, and novel approaches that minimize the emergence of resistant pathogens are desperately needed. Antimicrobial peptides are newer therapeutics that attempt to do this; however, they fall short because of low to moderate antimicrobial activity, low protease stability, susceptibility to resistance development, and high cost of production. The recently developed random peptide mixtures (RPMs) are promising alternatives. RPMs are synthesized by incorporating a defined proportion of two amino acids at each coupling step rather than just one, making them highly variable but still defined in their overall composition, chain length, and stereochemistry. Because RPMs have extreme diversity, it is unlikely that bacteria would be capable of rapidly evolving resistance. However, their efficacy against pathogens in animal models of human infectious diseases remained uncharacterized. Here, we demonstrated that RPMs have strong safety and pharmacokinetic profiles. RPMs rapidly killed both Pseudomonas aeruginosa and Staphylococcus aureus efficiently and disrupted preformed biofilms by both pathogens. Importantly, RPMs were efficacious against both pathogens in mouse models of bacteremia and acute pneumonia. Our results demonstrate that RPMs are potent broad-spectrum therapeutics against antibiotic-resistant pathogens.


Assuntos
Anti-Infecciosos , Bacteriemia , Staphylococcus aureus Resistente à Meticilina , Pneumonia , Animais , Bacteriemia/tratamento farmacológico , Camundongos , Peptídeos , Pseudomonas aeruginosa
3.
Pharmaceutics ; 12(12)2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-33271900

RESUMO

Mycobacterium bovis (M. bovis) is a member of the Mycobacterium tuberculosis complex imposing a high zoonotic threat to human health. The limited efficacy of BCG (Bacillus Calmette-Guérin) and upsurges of drug-resistant tuberculosis require new effective vaccination approaches and anti-TB drugs. Poly (lactic-co-glycolic acid) (PLGA) is a preferential drug delivery system candidate. In this study, we formulated PLGA nanoparticles (NPs) encapsulating the recombinant protein bovine neutrophil ß-defensin-5 (B5), and investigated its role in immunomodulation and antimicrobial activity against M. bovis challenge. Using the classical water-oil-water solvent-evaporation method, B5-NPs were prepared, with encapsulation efficiency of 85.5% ± 2.5%. These spherical NPs were 206.6 ± 26.6 nm in diameter, with a negatively charged surface (ζ-potential -27.1 ± 1.5 mV). The encapsulated B5 protein from B5-NPs was released slowly under physiological conditions. B5 or B5-NPs efficiently enhanced the secretion of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß and IL-10 in J774A.1 macrophages. B5-NPs-immunized mice showed significant increases in the production of TNF-α and immunoglobulin A (IgA) in serum, and the proportion of CD4+ T cells in spleen compared with B5 alone. In immunoprotection studies, B5-NPs-immunized mice displayed significant reductions in pulmonary inflammatory area, bacterial burden in the lungs and spleen at 4-week after M. bovis challenge. In treatment studies, B5, but not B5-NPs, assisted rifampicin (RIF) with inhibition of bacterial replication in the lungs and spleen. Moreover, B5 alone also significantly reduced the bacterial load in the lungs and spleen. Altogether, our findings highlight the significance of the B5-PLGA NPs in terms of promoting the immune effect of BCG and the B5 in enhancing the therapeutic effect of RIF against M. bovis.

4.
Virulence ; 11(1): 1090-1107, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32842850

RESUMO

The virulence behaviors of many Gram-negative bacterial pathogens are governed by quorum-sensing (QS), a hierarchical system of gene regulation that relies on population density by producing and detecting extracellular signaling molecules. Although extensively studied under in vitro conditions, adaptation of QS system to physiologically relevant host environment is not fully understood. In this study, we investigated the influence of lung environment on the regulation of Pseudomonas aeruginosa virulence factors by QS in a mouse model of acute pneumonia. When cultured under laboratory conditions in lysogeny broth, wild-type P. aeruginosa strain PAO1 began to express QS-regulated virulence factors elastase B (LasB) and rhamnolipids (RhlA) during transition from late-exponential into stationary growth phase. In contrast, during acute pneumonia as well as when cultured in mouse bronchial alveolar lavage fluids (BALF), exponential phase PAO1 bacteria at low population density prematurely expressed QS regulatory genes lasI-lasR and rhlI-rhlR and their downstream virulence genes lasB and rhlA. Further analysis indicated that surfactant phospholipids were the primary components within BALF that induced the synthesis of N-(3-oxododecanoyl)-L-homoserine lactone (C12-HSL), which triggered premature expression of LasB and RhlA. Both phenol extraction and phospholipase A2 digestion abolished the ability of mouse BALF to promote LasB and RhlA expression. In contrast, provision of the major surfactant phospholipid dipalmitoylphosphatidylcholine (DPPC) restored the expression of both virulence factors. Collectively, our study demonstrates P. aeruginosa modulates its QS to coordinate the expression of virulence factors during acute pneumonia by recognizing pulmonary surfactant phospholipids.


Assuntos
Fosfolipídeos/metabolismo , Pseudomonas aeruginosa/patogenicidade , Percepção de Quorum , Fatores de Virulência/genética , Animais , Proteínas de Bactérias/genética , Estudos de Coortes , Feminino , Regulação Bacteriana da Expressão Gênica , Masculino , Camundongos , Pneumonia Bacteriana/microbiologia , Pseudomonas aeruginosa/genética , Surfactantes Pulmonares/metabolismo , Virulência/genética , Fatores de Virulência/metabolismo
5.
Environ Res ; 191: 110054, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32827520

RESUMO

In this paper, a comparative study on removal of the emerging pollutant phenazone (PNZ) by two treatment processes UVA/Fe(II)/persulfate (PS) and UVA/Fe(II)/peroxymonosulfate (PMS) was conducted. The two processes showed high efficiency in PNZ degradation, followed by a reasonable mineralization. The treatment system with PMS was found to be more efficient for PNZ degradation than that with PS due to the larger amounts of radicals generated. While the treatment process UVA/Fe(II)/PS showed higher ΔTOC/ΔSMX (TOC removal per unit of PNZ decay) than UVA/Fe(II)/PMS process. The sulfate and hydroxyl radicals played dominant roles in PNZ degradation in the UVA/Fe(II)/PS and UVA/Fe(II)/PMS process, respectively. Six and seven intermediates during PNZ degradation by UVA/Fe(II)/PS and UVA/Fe(II)/PMS process were detected, respectively. Among the detected intermediates, six of them are found for the first time. It takes shorter time for toxicity elimination by UVA/Fe(II)/PS process than UVA/Fe(II)/PMS, possibly due to the lower Kow values of hydroxylated products. The results demonstrate that UVA/Fe(II)/PMS process is more efficient in PNZ degradation, while UVA/Fe(II)/PS is more efficient in detoxification of PNZ. The two sulfate radicals based processes have good potentials in degradation, mineralization and detoxification of the emerging contaminants such as PNZ.


Assuntos
Poluentes Ambientais , Poluentes Químicos da Água , Antipirina , Radical Hidroxila , Oxirredução , Sulfatos
6.
Mucosal Immunol ; 13(4): 637-651, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034274

RESUMO

Goblet cell hyperplasia and metaplasia and excessive mucus are prominent pathologies of chronic airway diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchitis. Chronic infection by respiratory pathogens, including Pseudomonas aeruginosa, exacerbates cyclical proinflammatory responses and mucus hypersecretion. P. aeruginosa and its virulence factor pyocyanin contribute to these pathologies by inhibiting FOXA2, a key transcriptional regulator of mucus homeostasis, through activation of antagonistic signaling pathways EGFR-AKT/ERK1/2 and IL-4/IL-13-STAT6-SPDEF. However, FOXA2-targeted therapy has not been previously explored. Here, we examined the feasibility of repurposing the incretin mimetic Exendin-4 to restore FOXA2-mediated airway mucus homeostasis. We have found that Exendin-4 restored FOXA2 expression, attenuated mucin production in COPD and CF-diseased airway cells, and reduced mucin and P. aeruginosa burden in mouse lungs. Mechanistically, Exendin-4 activated the GLP1R-PKA-PPAR-γ-dependent phosphatases PTEN and PTP1B, which inhibited key kinases within both EGFR and STAT6 signaling cascades. Our results may lead to the repurposing of Exendin-4 and other incretin mimetics to restore FOXA2 function and ultimately regulate excessive mucus in diseased airways.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Exenatida/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Fator 3-beta Nuclear de Hepatócito/metabolismo , Homeostase , PPAR gama/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Suscetibilidade a Doenças , Receptores ErbB/metabolismo , Expressão Gênica , Fator 3-beta Nuclear de Hepatócito/genética , Humanos , Modelos Biológicos , Mucinas/genética , Mucinas/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Fator de Transcrição STAT6/metabolismo
7.
Infect Immun ; 88(4)2020 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-31988172

RESUMO

The competence regulon of pneumococcus regulates both genetic transformation and virulence. However, competence induction during host infection has not been examined. By using the serotype 2 strain D39, we transcriptionally fused the firefly luciferase (luc) to competence-specific genes and spatiotemporally monitored the competence development in a mouse model of pneumonia-derived sepsis. In contrast to the universally reported short transient burst of competent state in vitro, the naturally developed competent state was prolonged and persistent during pneumonia-derived sepsis. The competent state began at approximately 20 h postinfection (hpi) and facilitated systemic invasion and sepsis development and progressed in different manners. In some mice, acute pneumonia quickly led to sepsis and death, accompanied by increasing intensity of the competence signal. In the remaining mice, pneumonia lasted longer, with the competence signal decreasing at first but increasing as the infection became septic. The concentration of pneumococcal inoculum (1 × 106 to 1 × 108 CFU/mouse) and postinfection lung bacterial burden did not appreciably impact the kinetics of competence induction. Exogenously provided competence stimulating peptide 1 (CSP1) failed to modulate the onset kinetics of competence development in vivo The competence shutoff regulator DprA was highly expressed during pneumonia-derived sepsis but failed to turn off the competent state in mice. Competent D39 bacteria propagated the competence signal through cell-to-cell contact rather than the classically described quorum-sensing mechanism. Finally, clinical pneumococcal strains of different serotypes were also able to develop natural competence during pneumonia-derived sepsis.


Assuntos
Competência de Transformação por DNA , Pneumonia Pneumocócica/complicações , Pneumonia Pneumocócica/microbiologia , Sepse/microbiologia , Streptococcus pneumoniae/crescimento & desenvolvimento , Streptococcus pneumoniae/genética , Animais , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Camundongos , Virulência
8.
Proc Natl Acad Sci U S A ; 117(3): 1689-1699, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31915298

RESUMO

Streptococcus pneumoniae is an opportunistic human pathogen that utilizes the competence regulon, a quorum-sensing circuitry, to acquire antibiotic resistance genes and initiate its attack on the human host. Interception of the competence regulon can therefore be utilized to study S. pneumoniae cell-cell communication and behavioral changes, as well as attenuate S. pneumoniae infectivity. Herein we report the design and synthesis of cyclic dominant negative competence-stimulating peptide (dnCSP) analogs capable of intercepting the competence regulon in both S. pneumoniae specificity groups with activities at the low nanomolar range. Structural analysis of lead analogs provided important insights as to the molecular mechanism that drives CSP receptor binding and revealed that the pan-group cyclic CSPs exhibit a chimeric hydrophobic patch conformation that resembles the hydrophobic patches required for both ComD1 and ComD2 binding. Moreover, the lead cyclic dnCSP, CSP1-E1A-cyc(Dap6E10), was found to possess superior pharmacological properties, including improved resistance to enzymatic degradation, while remaining nontoxic. Lastly, CSP1-E1A-cyc(Dap6E10) was capable of attenuating mouse mortality during acute pneumonia caused by both group 1 and group 2 S. pneumoniae strains. This cyclic pan-group dnCSP is therefore a promising drug lead scaffold against S. pneumoniae infections that could be administered individually or utilized in combination therapy to augment the effects of current antimicrobial agents.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/farmacologia , Percepção de Quorum/efeitos dos fármacos , Streptococcus pneumoniae/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Infecções Pneumocócicas/tratamento farmacológico , Ligação Proteica , Regulon/efeitos dos fármacos
9.
Infect Immun ; 87(11)2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31451619

RESUMO

Streptococcus pneumoniae (pneumococcus) causes multiple infectious diseases. The pneumococcal competence system facilitates genetic transformation, spreads antibiotic resistance, and contributes to virulence. DNA-processing protein A (DprA) regulates the exit of pneumococcus from the competent state. Previously, we have shown that DprA is important in both bacteremia and pneumonia infections. Here, we examined the mechanisms of virulence attenuation in a ΔdprA mutant. Compared to the parental wild-type D39, the ΔdprA mutant enters the competent state when exposed to lower concentrations of the competence-stimulating peptide CSP1. The ΔdprA mutant overexpresses ComM, which delays cell separation after division. Additionally, the ΔdprA mutant overexpresses allolytic factors LytA, CbpD, and CibAB and is more susceptible to detergent-triggered lysis. Disabling of the competent-state-specific induction of ComM and allolytic factors compensated for the virulence loss in the ΔdprA mutant, suggesting that overexpression of these factors contributes to virulence attenuation. Finally, the ΔdprA mutant fails to downregulate the expression of multiple competence-regulated genes, leading to the excessive energy consumption. Collectively, these results indicate that an inability to properly exit the competent state disrupts multiple cellular processes that cause virulence attenuation in the ΔdprA mutant.


Assuntos
Proteínas de Bactérias/metabolismo , Proteínas de Membrana/metabolismo , Streptococcus pneumoniae/genética , Animais , Proteínas de Bactérias/genética , Feminino , Deleção de Genes , Regulação Bacteriana da Expressão Gênica , Masculino , Proteínas de Membrana/genética , Camundongos , Nasofaringe/microbiologia , Pneumonia Pneumocócica/microbiologia
10.
Cell Microbiol ; 21(1): e12957, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30221439

RESUMO

Because of exposure to environmental pollutants, infectious agents, and genetic predisposition, companion animals develop respiratory illnesses similar to those in humans. Older dogs of smaller breeds develop canine infectious respiratory disease, chronic bronchitis, and chronic obstructive pulmonary disease, with chronic lung infection, airway goblet cell hyperplasia and metaplasia, and mucus hypersecretion. Excessive mucus clogs airways, reduces gas exchanges, disables the mucociliary clearance, and reduces drug penetration. The Forkhead box protein A2 (FOXA2) is a key transcriptional regulator that maintains airway mucus homeostasis. Prior studies have shown that FOXA2 expression is frequently depleted in diseased human airways. Unfortunately, FOXA2 depletion has not been examined in dogs. Our current study indicated that both single bacterial infection by Pseudomonas aeruginosa and Bordetella bronchiseptica and polymicrobial infection by viral/bacterial pathogens depleted FOXA2 in canine airways, resulting in goblet cell hyperplasia and metaplasia and excessive mucus production. Furthermore, P. aeruginosa virulence factor pyocyanin activated the antagonistic STAT6 and epidermal growth factor receptor signalling pathways to inhibit FOXA2. Unravelling the mechanism of FOXA2 inactivation will hasten the development of non-antibiotic therapeutics to improve mucociliary clearance of pathogens in canine airway.


Assuntos
Bronquite/patologia , Células Caliciformes/patologia , Fator 3-beta Nuclear de Hepatócito/metabolismo , Muco/metabolismo , Mucosa Respiratória/patologia , Animais , Infecções por Bordetella/patologia , Modelos Animais de Doenças , Cães , Infecções por Pseudomonas/patologia , Viroses/patologia
11.
Chembiochem ; 19(22): 2380-2386, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30211457

RESUMO

Streptococcus pneumoniae (pneumococcus) is a prevalent human pathogen responsible for a variety of diseases, including pneumonia, bacteremia, sepsis, meningitis and otitis media, with a death toll of >22 000 a year in the United States alone. Pneumococcus uses the competence regulon and its associated signaling peptide, the competence stimulating peptide (CSP), to initiate its attack on the host and establish an infection. In this work, we set out to: 1) develop a pan-group quorum sensing inhibitor that could effectively interact with both the pneumococcus ComD1 and ComD2 receptors; and 2) evaluate the utility of dominant-negative CSPs (dnCSPs) in attenuating pneumococcus infectivity. Our results highlight the potential of inhibiting the competence regulon as a therapeutic approach to combat pneumococcus infections.


Assuntos
Proteínas de Bactérias , Pneumonia Pneumocócica , Percepção de Quorum/efeitos dos fármacos , Streptococcus pneumoniae , Doença Aguda , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/farmacologia , Modelos Animais de Doenças , Humanos , Camundongos , Terapia de Alvo Molecular , Pneumonia Pneumocócica/tratamento farmacológico , Pneumonia Pneumocócica/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/patogenicidade , Virulência
12.
Mucosal Immunol ; 9(4): 1039-1050, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26555707

RESUMO

Cystic fibrosis (CF) patients battle life-long pulmonary infections with the respiratory pathogen Pseudomonas aeruginosa (PA). An overabundance of mucus in CF airways provides a favorable niche for PA growth. When compared with that of non-CF individuals, mucus of CF airways is enriched in sialyl-Lewis(x), a preferred binding receptor for PA. Notably, the levels of sialyl-Lewis(x) directly correlate with infection severity in CF patients. However, the mechanism by which PA causes increased sialylation remains uncharacterized. In this study, we examined the ability of PA virulence factors to modulate sialyl-Lewis(x) modification in airway mucins. We found pyocyanin (PCN) to be a potent inducer of sialyl-Lewis(x) in both mouse airways and in primary and immortalized CF and non-CF human airway epithelial cells. PCN increased the expression of C2/4GnT and ST3Gal-IV, two of the glycosyltransferases responsible for the stepwise biosynthesis of sialyl-Lewis(x), through a tumor necrosis factor (TNF)-α-mediated phosphoinositol-specific phospholipase C (PI-PLC)-dependent pathway. Furthermore, PA bound more efficiently to airway epithelial cells pre-exposed to PCN in a flagellar cap-dependent manner. Importantly, antibodies against sialyl-Lewis(x) and anti-TNF-α attenuated PA binding. These results indicate that PA secretes PCN to induce a favorable environment for chronic colonization of CF lungs by increasing the glycosylation of airway mucins with sialyl-Lewis(x).


Assuntos
Fibrose Cística/imunologia , Mucinas/metabolismo , Oligossacarídeos/metabolismo , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/imunologia , Piocianina/metabolismo , Mucosa Respiratória/metabolismo , Animais , Aderência Bacteriana , Linhagem Celular Tumoral , Fibrose Cística/microbiologia , Glicosilação , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Respiratória/patologia , Antígeno Sialil Lewis X , Sialiltransferases/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fosfolipases Tipo C/metabolismo
13.
Curr Genet ; 62(1): 97-103, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26403231

RESUMO

Horizontal gene transfer mediated by the competence regulon is a major driver of genome plasticity in Streptococcus pneumoniae. When pneumococcal cells enter the competent state, about 6% of the genes in the genome are up-regulated. Among these, some genes are essential for genetic transformation while others are dispensable for the process. Exhaustive deletion analyses show that some up-regulated genes dispensable for genetic transformation contribute to pneumococcal-mediated pneumonia and bacteremia infections. Interestingly, virulence functions of such genes are either dependent or independent of the competent state. Among the competent-state-dependent genes are those mediating allolysis, a process where small fraction of non-competent cells within the pneumococcal population are lysed by their competent counterparts, releasing DNA presumably for transformation. Inadvertently, the pore-forming toxin pneumolysin is also released during allolysis, contributing to virulence. In this review, we discuss recent advances in our understanding of pneumococcal virulence processes mediated by the competence regulon. We proposed that coupling of competence induction and bacterial fitness drives the natural selection to favor an intact competence regulon, which in turn, provides the long-term benefits of genetic plasticity.


Assuntos
Transferência Genética Horizontal , Streptococcus pneumoniae/fisiologia , Transformação Bacteriana , Animais , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Genes Bacterianos , Humanos , Mutação , Óperon , Recombinação Genética , Streptococcus pneumoniae/patogenicidade , Estreptolisinas/genética , Estreptolisinas/metabolismo , Virulência/genética
14.
Mol Microbiol ; 97(1): 151-65, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25846124

RESUMO

The competence regulon of Streptococcus pneumoniae (pneumococcus) is crucial for genetic transformation. During competence development, the alternative sigma factor ComX is activated, which in turn, initiates transcription of 80 'late' competence genes. Interestingly, only 16 late genes are essential for genetic transformation. We hypothesized that these late genes that are dispensable for competence are beneficial to pneumococcal fitness during infection. These late genes were systematically deleted, and the resulting mutants were examined for their fitness during mouse models of bacteremia and acute pneumonia. Among these, 14 late genes were important for fitness in mice. Significantly, deletion of some late genes attenuated pneumococcal fitness to the same level in both wild-type and ComX-null genetic backgrounds, suggesting that the constitutive baseline expression of these genes was important for bacterial fitness. In contrast, some mutants were attenuated only in the wild-type genetic background but not in the ComX-null background, suggesting that specific expression of these genes during competence state contributed to pneumococcal fitness. Increased virulence during competence state was partially caused by the induction of allolytic enzymes that enhanced pneumolysin release. These results distinguish the role of basal expression versus competence induction in virulence functions encoded by ComX-regulated late competence genes.


Assuntos
Competência de Transformação por DNA/genética , Deleção de Genes , Infecções Pneumocócicas/microbiologia , Streptococcus pneumoniae/genética , Streptococcus pneumoniae/patogenicidade , Animais , Bacteriemia/microbiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Modelos Animais de Doenças , Regulação Bacteriana da Expressão Gênica , Aptidão Genética , Camundongos , Mutação , Pneumonia Pneumocócica/microbiologia , Regulon , Estreptolisinas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Virulência/genética
15.
Vet Immunol Immunopathol ; 163(3-4): 146-56, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25550244

RESUMO

As innate immune cells, macrophages are expected to respond to mycobacterial infection equally in both Mycobacterium bovis-infected cows and healthy cows. We previously found that monocyte-derived macrophages (MDMs) from M. bovis-infected cows respond differently than MDMs from healthy cows when exposed to in vitro M. bovis challenge. We have now used the Agilent™ Bovine Gene Expression Microarray to examine transcriptional differences between these MDMs. At a high multiplicity of infection (10), in vitro challenge led to changes in several thousands of genes, with dysregulation at multiple orders of magnitude. For example, significant changes were seen for colony stimulating factor 3 (granulocyte) (CSF3), colony stimulating factor 2 (granulocyte-macrophage) (CSF2), and chemokine (C-C motif) ligand 20 (CCL20). Classical macrophage activation was also observed, although to a lesser degree in interleukin 12 (IL12) expression. For macrophages, kallikrein-related peptidase 12 (KLK12) and protease, serine, 2 (trypsin 2) (PRSS2), as well as a secreted protein, acidic, cysteine-rich (osteonectin) (SPARC)-centered matricellular gene network, were differentially expressed in infected animals. Finally, global transcriptome fold-changes caused by in vitro challenge were higher in healthy cows than in tuberculosis-positive cows, suggesting that healthy macrophages responded marginally better to in vitro infection. Macrophages from healthy and already infected animals can both be fully activated during M. bovis infection, yet there are differences between these macrophages: distinct expression pattern in matricellular proteins, and their different responses to in vitro infection.


Assuntos
Regulação da Expressão Gênica/imunologia , Macrófagos/metabolismo , Mycobacterium bovis/fisiologia , Transcriptoma/imunologia , Tuberculose Bovina/metabolismo , Animais , Estudos de Casos e Controles , Bovinos , Feminino , Macrófagos/microbiologia , Análise Serial de Proteínas
16.
DNA Cell Biol ; 33(5): 311-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24568683

RESUMO

Mycobacterium bovis is the etiological factor of bovine tuberculosis (BTB), posing a significant problem to domestic cattle. The bacterium is also zoonotic, affecting human health worldwide. Macrophage evasion of the bacterium involves mycobacterial molecules such as MB1684 (ornithine carbamoyltransferase). In this study, we confirmed a concentration-dependent decrease in proliferation of Ana-1 macrophages when treated with rMB1684 when compared with mycobacterium bovis purified protein derivative of tuberculosis (MbPPD) or phosphate buffer solution incubation groups. We examined the activation of nuclear factor-kappa B (NF-κB) upon exposure to MB1684, and its role in MB1684-induced upregulation of interferon (IFN)-γ and proinflammatory cytokines (interleukin [IL]-1ß, IL-6, and tumor necrosis factor-α) in Ana-1 macrophages. The levels of proinflammatory cytokines and IFN-γ were significantly high in MB1684-treated Ana-1 macrophages. The treatment led to an increase in NF-κB activation and a high expression of the just mentioned proinflammatory cytokines. NF-κB inhibition significantly abrogated MB1684-induced upregulation of proinflammatory cytokine mRNA expression, which suggests that MB1684-induced activation of NF-κB in turn stimulates gene expression of IFN-γ and proinflammatory cytokines in Ana-1 macrophages. The experiment was repeated in bone marrow macrophages, a more in-vivo-like model system, and similar results validated our conclusion. Further, we identified the possibility of the application of MB1684 antigen for the detection of BTB in cattle serum.


Assuntos
Proteínas de Bactérias/farmacologia , Macrófagos/efeitos dos fármacos , Mycobacterium bovis/enzimologia , NF-kappa B/metabolismo , Ornitina Carbamoiltransferase/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Macrófagos/metabolismo , Macrófagos/fisiologia , Camundongos , NF-kappa B/genética
17.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 9): m1294-5, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22058883

RESUMO

In the title one-dimensional coordination polymer, {[Eu(C(9)H(4)N(2)O(4))(C(9)H(5)N(2)O(4))(H(2)O)(3)]·2H(2)O}(n), one of the 1H-benzimidazole-5,6-dicarboxyl-ate (Hbdc) ligands is protonated at the imidazole group (H(2)bdc). The Eu(III) ion is eight-coordinated by two O atoms from two Hbdc ligands, three O atoms from two H(2)bdc ligands and three water mol-ecules, showing a distorted square-anti-prismatic geometry. The Eu(III) ions are bridged by the carboxyl-ate groups of the Hbdc and H(2)bdc ligands, forming a chain along [110], with an Eu⋯Eu separation of 5.4594 (3) Å. These chains are further connected by inter-molecular O-H⋯O, N-H⋯O and N-H⋯N hydrogen bonds, as well as π-π inter-actions between the imidazole and benzene rings [centroid-centroid distances = 3.558 (3), 3.906 (2), 3.397 (3), 3.796 (2) and 3.898 (2) Å], into a three-dimensional supra-molecular network.

18.
Acta Crystallogr Sect E Struct Rep Online ; 67(Pt 9): m1310-1, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-22058892

RESUMO

In the title coordination polymer, catena-poly[[[triaqua-europium(III)]-bis-(µ-1H,3H-benzimidazol-3-ium-5,6-dicarb-oxyl-ato-κ(3)O(5),O(5'):O(6))-[triaqua-europium(III)]-di-µ-sulfato-κ(3)O:O,O';κ(3)O,O':O'] hexahydrate], [Eu(2)(C(9)H(5)N(2)O(4))(2)(SO(4))(2)(H(2)O)(6)]·6H(2)O}(n), the 1H,3H-benzimidazol-3-ium-5,6-dicarb-oxy-l-ate ligand is protonated at the imidazole group (H(2)bdc). The Eu(III) ion is coordinated by nine O atoms from two H(2)bdc ligands, two sulfate anions and three water mol-ecules, displaying a bicapped trigonal prismatic geometry. The carboxyl-ate groups of the H(2)bdc ligands and the sulfate anions link the Eu(III) ions, forming a chain along [010]. These chains are further connected by N-H⋯O and O-H⋯O hydrogen bonds and π-π inter-actions between the imidazole and benzene rings [centroid-centroid distances = 3.997 (4), 3.829 (4) and 3.573 (4) Å] into a three-dimensional supra-molecular network.

19.
FEMS Microbiol Lett ; 321(1): 30-6, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21569079

RESUMO

Bovine tuberculosis (BTB) is a chronic infectious disease caused by the pathogen Mycobacterium bovis and poses a long-standing threat to livestock worldwide. To further elucidate the poorly defined BTB immune response in cattle, we utilized monocyte-derived macrophages (MDMs) to assess the gene expression related to M. bovis Beijing strain stimulation. Here, we demonstrate the existence of distinctive gene expression patterns between macrophages of healthy cattle and those exposed to BTB. In comparing MDMs cells from healthy cattle (n=5) and cattle with tuberculosis (n=5) 3 h after M. bovis stimulation, the differential expressions of seven genes (IL1ß, IL1R1, IL1A, TNF-α, IL10, TLR2 and TLR4) implicated in M. bovis response were examined. The expressions of these seven genes were increased in both the tuberculosis-infected and the healthy cattle to M. bovis stimulation, and two of them (TLR2 and IL10) were significantly different in the tuberculosis and the healthy control groups (P≤0.05). The increase in the expression of the TLR2 gene is more significant in healthy cattle response to stimulation, and the change of IL10 gene expression is more significant in tuberculosis cattle. Additionally, we investigated the cytopathic effect caused by M. bovis stimulation and the relationship between M. bovis and MDMs cells to obtain a general profile of pathogen-host interaction.


Assuntos
Regulação da Expressão Gênica , Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium bovis/fisiologia , Tuberculose Bovina/imunologia , Animais , Bovinos , Contagem de Colônia Microbiana , Citocinas/imunologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno/imunologia , Espaço Intracelular/microbiologia , Macrófagos/patologia , Mycobacterium bovis/crescimento & desenvolvimento , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Tuberculose Bovina/patologia
20.
Yan Ke Xue Bao ; 20(3): 155-7, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15499722

RESUMO

PURPOSE: To analyze the clinic manifestation and prognosis of Behçet disease. METHOD: Twenty patients requiring inpatient treatment with Behçet disease were retrospectively analyzed. RESULTS: The morbidity of Behçet disease is 5.5/100 000. In the systemic damage, stomatocace and skin lesion are 95%, eye lesion and genital ulcer 50%, joint lesion 45%, gastrointestinal lesion 35%, Uveitis is the major disease in eye lesion, and followed in order by retinal vasculitis and obstruction of retinal artery. Attack age average 30.3 years old. Diagnosis age average 34.8 years old. The patients stay in hospital for 41 days on the average. Cure rate is 55%, improvement rate 40%, blinding rate of eye lesion is 36%. CONCLUSIONS: Behçet disease is a multisystem lesion disease. Stomatocace and skin lesion is the major lesion, the next in common occurrence are eye and genital lesions. Repeated attack of uveitis, complicated cataract and secondary glaucoma are the major causes of blindness.


Assuntos
Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Adolescente , Adulto , Síndrome de Behçet/complicações , Síndrome de Behçet/epidemiologia , Catarata/epidemiologia , Catarata/etiologia , China/epidemiologia , Ciclofosfamida/uso terapêutico , Feminino , Glaucoma/epidemiologia , Glaucoma/etiologia , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Uveíte/epidemiologia , Uveíte/etiologia , Acuidade Visual
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