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1.
Front Bioeng Biotechnol ; 12: 1390513, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38978720

RESUMO

UV-stabilizers are a class of additives that provide extended polymer resistance to UV-degradation, but have also been suggested to have antimicrobial activity, potentially preventing the spread of pathogens, and inhibiting microbial-induced biodegradation. In this work, we incorporated different UV-stabilizers, a hindered amine light stabilizer (HALS), Tinuvin 770 DF and Tinuvin PA 123, or a hybrid HALS/UV-absorber, Tinuvin 5151, in polyurethane formulations to produce lacquer-films, and tested their antimicrobial activity against Staphylococcus aureus (methicillin-resistant and -sensitive strains), Escherichia coli and Candida albicans. Lacquer-films incorporated with Tinuvin 770 DF showed strong antimicrobial performance against bacteria and fungi, while maintaining cytocompatibility. The mechanism of action revealed a positive relationship between Tinuvin 770 DF concentration, microbial death, and reactive nitrogen species (RNS), suggesting that RNS produced during autoxidation of Tinuvin 770 DF is responsible for the antimicrobial properties of this UV-stabilizer. Conversely, lacquer-films incorporated with Tinuvin 5151 or Tinuvin PA 123 exhibited no antimicrobial properties. Collectively, these results highlight the commercial potential of Tinuvin 770 DF to prevent photo- and biodegradation of polymers, while also inhibiting the spread of potentially harmful pathogens. Furthermore, we provide a better understanding of the mechanism underlying the biocidal activity of HALS associated to autooxidation of the amine group.

2.
Cells ; 13(8)2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38667269

RESUMO

Fabry Disease (FD) is one of the most prevalent lysosomal storage disorders, resulting from mutations in the GLA gene located on the X chromosome. This genetic mutation triggers glo-botriaosylceramide (Gb-3) buildup within lysosomes, ultimately impairing cellular functions. Given the role of lysosomes in immune cell physiology, FD has been suggested to have a profound impact on immunological responses. During the past years, research has been focusing on this topic, and pooled evidence strengthens the hypothesis that Gb-3 accumulation potentiates the production of pro-inflammatory mediators, revealing the existence of an acute inflammatory process in FD that possibly develops to a chronic state due to stimulus persistency. In parallel, extracellular vesicles (EVs) have gained attention due to their function as intercellular communicators. Considering EVs' capacity to convey cargo from parent to distant cells, they emerge as potential inflammatory intermediaries capable of transporting cytokines and other immunomodulatory molecules. In this review, we revisit the evidence underlying the association between FD and altered immune responses and explore the potential of EVs to function as inflammatory vehicles.


Assuntos
Exossomos , Doença de Fabry , Inflamação , Doença de Fabry/genética , Doença de Fabry/metabolismo , Doença de Fabry/patologia , Humanos , Inflamação/patologia , Exossomos/metabolismo , Animais , Vesículas Extracelulares/metabolismo
3.
Eur J Med Chem ; 268: 116297, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38458108

RESUMO

A series of novel 9-alkyl/aryl-2-aryl-6-carbamoylpurines were synthesized, and their activity against Mycobacterium tuberculosis strain H37Rv was assessed. The SAR analysis on the first set of derivatives, with an alkyl or aryl unit at N-9 and a phenolic unit at C-2, showed that the activity depends on the purine ring substituents at N-9 and C-2. A phenyl group at N-9 combined with a 3-hydroxyphenyl or 4-hydroxyphenyl at C-2 improve the activity. The most active compound of this set has a phenyl group at N-9 and a 4-hydroxyphenyl group at C-2, displaying an IC90 = 1.2 µg/mL and a selectivity index higher than 25.5. This compound served as a Hit to design the second set of derivatives. A phenyl group at N-9 was maintained, and the group at C-2 was diversified. The SAR analysis showed that the aryl unit at C-2 must have an oxygen or nitrogen atom bonded in the para position. A proton, a small alkyl or a substituted aryl group may also be bonded to the oxygen. The compound with the 4-methoxyphenyl group at C-2, 1Bd, exhibits the highest activity with an IC90 < 0.19 µg/mL. This compound is highly potent against M. tuberculosis strain H37Rv and non-toxic for VERO mammalian cells with an SI > 153.8. Compound 1Bd was also non-cytotoxic against primary macrophage cultures at IC90, 2xIC90, and 10xIC90 and significantly reduced the bacterial load in M. tuberculosis-infected macrophages at the same concentrations. Compound 1Bd showed a favorable pharmacokinetic profile when administered orally, with major lung and liver accumulation. In vivo antimycobacterial efficacy of 1Bd was tested at 25 mg/kg. At the tested regimen, a decrease in bacterial burden was observed in the liver. Optimization of the treatment regimen should be performed to fully potentiate the in vivo efficacy of our lead molecule, particularly in the lung, the main target organ of M. tuberculosis.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Antituberculosos/farmacologia , Testes de Sensibilidade Microbiana , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Oxigênio , Relação Estrutura-Atividade , Mamíferos
4.
Front Microbiol ; 14: 1266261, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37840746

RESUMO

Mycobacterium ulcerans causes Buruli Ulcer, a neglected infectious skin disease that typically progresses from an early non-ulcerative lesion to an ulcer with undermined edges. If not promptly treated, these lesions can lead to severe disfigurement and disability. The standard antibiotic regimen for Buruli Ulcer treatment has been oral rifampicin combined with intramuscular streptomycin administered daily for 8 weeks. However, there has been a recent shift toward replacing streptomycin with oral clarithromycin. Despite the advantages of this antibiotic regimen, it is limited by low compliance, associated side effects, and refractory efficacy for severe ulcerative lesions. Therefore, new drug candidates with a safer pharmacological spectrum and easier mode of administration are needed. Statins are lipid-lowering drugs broadly used for dyslipidemia treatment but have also been reported to have several pleiotropic effects, including antimicrobial activity against fungi, parasites, and bacteria. In the present study, we tested the susceptibility of M. ulcerans to several statins, namely atorvastatin, simvastatin, lovastatin and fluvastatin. Using broth microdilution assays and cultures of M. ulcerans-infected macrophages, we found that atorvastatin, simvastatin and fluvastatin had antimicrobial activity against M. ulcerans. Furthermore, when using the in vitro checkerboard assay, the combinatory additive effect of atorvastatin and fluvastatin with the standard antibiotics used for Buruli Ulcer treatment highlighted the potential of statins as adjuvant drugs. In conclusion, statins hold promise as potential treatment options for Buruli Ulcer. Further studies are necessary to validate their effectiveness and understand the mechanism of action of statins against M. ulcerans.

5.
Bioeng Transl Med ; 8(3): e10504, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37206216

RESUMO

Diabetic foot infection (DFI) is an important cause of morbidity and mortality. Antibiotics are fundamental for treating DFI, although bacterial biofilm formation and associated pathophysiology can reduce their effectiveness. Additionally, antibiotics are often associated with adverse reactions. Hence, improved antibiotic therapies are required for safer and effective DFI management. On this regard, drug delivery systems (DDSs) constitute a promising strategy. We propose a gellan gum (GG)-based spongy-like hydrogel as a topical and controlled DDS of vancomycin and clindamycin, for an improved dual antibiotic therapy against methicillin-resistant Staphylococcus aureus (MRSA) in DFI. The developed DDS presents suitable features for topical application, while promoting the controlled release of both antibiotics, resulting in a significant reduction of in vitro antibiotic-associated cytotoxicity without compromising antibacterial activity. The therapeutic potential of this DDS was further corroborated in vivo, in a diabetic mouse model of MRSA-infected wounds. A single DDS administration allowed a significant bacterial burden reduction in a short period of time, without exacerbating host inflammatory response. Taken together, these results suggest that the proposed DDS represents a promising strategy for the topical treatment of DFI, potentially overcoming limitations associated with systemic antibiotic administration and minimizing the frequency of administration.

6.
Front Microbiol ; 13: 989464, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36246265

RESUMO

Genome sequencing projects of humans and other organisms reinforced that the complexity of biological systems is largely attributed to the tight regulation of gene expression at the epigenome and RNA levels. As a consequence, plenty of technological developments arose to increase the sequencing resolution to the cell dimension creating the single-cell genomics research field. Single-cell RNA sequencing (scRNA-seq) is leading the advances in this topic and comprises a vast array of different methodologies. scRNA-seq and its variants are more and more used in life science and biomedical research since they provide unbiased transcriptomic sequencing of large populations of individual cells. These methods go beyond the previous "bulk" methodologies and sculpt the biological understanding of cellular heterogeneity and dynamic transcriptomic states of cellular populations in immunology, oncology, and developmental biology fields. Despite the large burden caused by mycobacterial infections, advances in this field obtained via single-cell genomics had been comparatively modest. Nonetheless, seminal research publications using single-cell transcriptomics to study host cells infected by mycobacteria have become recently available. Here, we review these works summarizing the most impactful findings and emphasizing the different and recent single-cell methodologies used, potential issues, and problems. In addition, we aim at providing insights into current research gaps and potential future developments related to the use of single-cell genomics to study mycobacterial infection.

7.
BMC Res Notes ; 15(1): 293, 2022 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-36071445

RESUMO

OBJECTIVE: Diabetic foot infection (DFI) represents a major healthcare burden, for which treatment is challenging owing to the pathophysiological alterations intrinsic to diabetes and the alarming increase of antimicrobial resistance. Novel therapies targeting DFI are therefore a pressing research need for which proper models of disease are required. RESULTS: Here, we present an optimized diabetic mouse model of methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds, that resemble key features of DFI, such as pathogen invasion through wound bed and surrounding tissue, necrosis, persistent inflammation and impaired wound healing. Thus, in a time-efficient manner and using simple techniques, this model represents a suitable approach for studying emerging therapies targeting DFI caused by MRSA.


Assuntos
Diabetes Mellitus , Pé Diabético , Staphylococcus aureus Resistente à Meticilina , Dermatopatias , Infecções Estafilocócicas , Animais , Pé Diabético/terapia , Modelos Animais de Doenças , Camundongos , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/terapia , Staphylococcus aureus , Úlcera
8.
Int J Pharm ; 623: 121954, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35760261

RESUMO

Skin infection by Mycobacterium ulcerans causes Buruli ulcer (BU) disease, a serious condition that significantly impact patient' health and quality of life and can be very difficult to treat. Treatment of BU is based on daily systemic administration of antibiotics for at least 8 weeks and presents drawbacks associated with the mode and duration of drug administration and potential side effects. Thus, new therapeutic strategies are needed to improve the efficacy and modality of BU therapeutics, resulting in a more convenient and safer antibiotic regimen. Hence, we developed a dual delivery system based on poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microparticles and a gellan gum (GG) hydrogel for delivery of rifampicin (RIF) and streptomycin (STR), two antibiotics used for BU treatment. RIF was successfully loaded into PHBV microparticles, with an encapsulation efficiency of 43%, that also revealed a mean size of 10 µm, spherical form and rough topography. These microparticles were further embedded in a GG hydrogel containing STR. The resultant hydrogel showed a porous microstructure that conferred a high water retention capability (superior to 2000%) and a controlled release of both antibiotics. Also, biological studies revealed antibacterial activity against M. ulcerans, and a good cytocompatibility in a fibroblast cell line. Thus, the proposed drug delivery system can constitute a potential topical approach for treatment of skin ulcers caused by BU disease.


Assuntos
Úlcera de Buruli , Antibacterianos/uso terapêutico , Úlcera de Buruli/tratamento farmacológico , Úlcera de Buruli/microbiologia , Humanos , Hidrogéis/uso terapêutico , Poliésteres/química , Qualidade de Vida , Rifampina , Estreptomicina
9.
Immunol Rev ; 301(1): 222-241, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33682158

RESUMO

Buruli ulcer is an emerging infectious disease associated with high morbidity and unpredictable outbreaks. It is caused by Mycobacterium ulcerans, a slow-growing pathogen evolutionarily shaped by the acquisition of a plasmid involved in the production of a potent macrolide-like cytotoxin and by genome rearrangements and downsizing. These events culminated in an uncommon infection pattern, whereby M. ulcerans is both able to induce the initiation of the inflammatory cascade and the cell death of its proponents, as well as to survive within the phagosome and in the extracellular milieu. In such extreme conditions, the host is sentenced to rely on a highly orchestrated genetic landscape to be able to control the infection. We here revisit the dynamics of M. ulcerans infection, drawing parallels from other mycobacterioses and integrating the most recent knowledge on its evolution and pathogenicity in its interaction with the host immune response.


Assuntos
Úlcera de Buruli , Mycobacterium ulcerans , Úlcera de Buruli/genética , Humanos , Mycobacterium ulcerans/genética
10.
Emerg Microbes Infect ; 10(1): 223-225, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33467983

RESUMO

Buruli ulcer (BU) is a devastating skin mycobacterial infection characterized by extensive cell death, which was previously suggested to be mediated by Bcl2-like protein 11 (BIM, encoded by the BCL2L11 gene). We here report the association of genetic variants in BCL2L11 with ulcerative forms of the disease in a cohort of 618 Beninese individuals. Our results show that regulation of apoptosis in humans contributes to BU lesions associated with worse prognosis, prompting for further investigation on the implementation of novel methods for earlier identification of at-risk patients.


Assuntos
Proteína 11 Semelhante a Bcl-2/genética , Úlcera de Buruli/genética , Proteína 11 Semelhante a Bcl-2/metabolismo , Úlcera de Buruli/metabolismo , Úlcera de Buruli/microbiologia , Estudos de Coortes , Predisposição Genética para Doença , Variação Genética , Humanos , Mycobacterium ulcerans/fisiologia , Polimorfismo de Nucleotídeo Único
11.
J Microbiol Biotechnol ; 31(2): 327-337, 2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33148943

RESUMO

Fibrinolytic enzymes with a direct mechanism of action and safer properties are currently requested for thrombolytic therapy. This paper reports on a new enzyme capable of degrading blood clots directly without impairing blood coagulation. This enzyme is also non-cytotoxic and constitutes an alternative to other thrombolytic enzymes known to cause undesired side effects. Twenty-four Bacillus isolates were screened for production of fibrinolytic enzymes using a fibrin agar plate. Based on produced activity, isolate S127e was selected and identified as B. subtilis using the 16S rDNA gene sequence. This strain is of biotechnological interest for producing high fibrinolytic yield and consequently has potential in the industrial field. The purified fibrinolytic enzyme has a molecular mass of 27.3 kDa, a predicted pI of 6.6, and a maximal affinity for Ala-Ala-Pro-Phe. This enzyme was almost completely inhibited by chymostatin with optimal activity at 48°C and pH 7. Specific subtilisin features were found in the gene sequence, indicating that this enzyme belongs to the BPN group of the S8 subtilisin family and was assigned as AprE127. This subtilisin increased thromboplastin time by 3.7% (37.6 to 39 s) and prothrombin time by 3.2% (12.6 to 13 s), both within normal ranges. In a whole blood euglobulin assay, this enzyme did not impair coagulation but reduced lysis time significantly. Moreover, in an in vitro assay, AprE127 completely dissolved a thrombus of about 1 cc within 50 min and, in vivo, reduced a thrombus prompted in a rat tail by 11.4% in 24 h compared to non-treated animals.


Assuntos
Bacillus subtilis/enzimologia , Proteínas de Bactérias/isolamento & purificação , Fibrinolíticos/isolamento & purificação , Subtilisinas/isolamento & purificação , Trombose/tratamento farmacológico , Animais , Bacillus subtilis/química , Bacillus subtilis/genética , Proteínas de Bactérias/administração & dosagem , Proteínas de Bactérias/química , Células Sanguíneas/efeitos dos fármacos , Células Sanguíneas/fisiologia , Coagulação Sanguínea/efeitos dos fármacos , Feminino , Fibrinolíticos/administração & dosagem , Fibrinolíticos/química , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Cinética , Peso Molecular , Tempo de Protrombina , Ratos , Ovinos , Subtilisinas/administração & dosagem , Subtilisinas/química , Trombose/fisiopatologia
12.
PLoS Negl Trop Dis ; 14(4): e0008161, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32267838

RESUMO

BACKGROUND: Buruli ulcer (BU) is a necrotizing skin disease, caused by Mycobacterium ulcerans, with poorly understood acquisition risk factors. This review aims at evaluating the importance of individual-sex, age, family ties with history of BU, gene variants-and clinical-Bacillus Calmette-Guérin (BCG) immunization, Human Immunodeficiency Virus (HIV) infection-variables in this process. METHODS: A systematic review was performed considering the following databases: ClinicalTrials.gov, Cochrane Controlled Register of Trials (CENTRAL), Current Contents Connect, Embase, MEDLINE, SciELO, Scopus and Web of Science. Eligible studies were critically appraised with The Joanna Briggs Institute checklists and heterogeneity was assessed with Cochran Q-test and I2 statistic. Published demographic data was descriptively analysed and clinical data pooled within random-effects modelling for meta-analysis. RESULTS: A total of 29 studies were included in the systematic review. Two randomized controlled trials (RCTs) and 21 case-control studies were selected for meta-analysis. Studies show that BU mainly affects age extremes, more preponderately males among children. Data pooled from RCTs do not reveal BCG to be protective against BU (odds ratio (OR) = 0.63; 95% CI = 0.38-1.05; I2 = 56%), a finding case-control studies appear to corroborate. HIV infection (OR = 6.80; 95% CI = 2.33-19.85; I2 = 0%) and SLC11A1 rs17235409 A allele (OR = 1.86; 95% CI = 1.25-2.77; I2 = 0%) are associated with increased prevalence of the disease. No definite conclusions can be drawn regarding the influence of previous family history of BU. DISCUSSION: While available evidence warrants further robustness, these results have direct implications on current interventions and future research programs, and foster the development of more cost-effective preventive and screening measures. REGISTRATION: The study was registered at PROSPERO with number CRD42019123611.


Assuntos
Úlcera de Buruli/fisiopatologia , Mycobacterium ulcerans/patogenicidade , Vacina BCG , Úlcera de Buruli/epidemiologia , Bases de Dados Factuais , Variação Genética , Infecções por HIV/complicações , Humanos , Anamnese
14.
PLoS Negl Trop Dis ; 13(8): e0007113, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31425525

RESUMO

Buruli Ulcer (BU) is a cutaneous disease caused by Mycobacterium ulcerans. The pathogenesis of this disease is closely related to the secretion of the toxin mycolactone that induces extensive destruction of the skin and soft tissues. Currently, there are no effective measures to prevent the disease and, despite availability of antibiotherapy and surgical treatments, these therapeutic options are often associated with severe side effects. Therefore, it is important to develop alternative strategies for the treatment of BU. Endolysins (lysins) are phage encoded enzymes that degrade peptidoglycan of bacterial cell walls. Over the past years, lysins have been emerging as alternative antimicrobial agents against bacterial infections. However, mycobacteria have an unusual outer membrane composed of mycolylarabinogalactan-peptidoglycan. To overcome this complex barrier, some mycobacteriophages encode a lipolytic enzyme, Lysin B (LysB). In this study, we demonstrate for the first time that recombinant LysB displays lytic activity against M. ulcerans isolates. Moreover, using a mouse model of M. ulcerans footpad infection, we show that subcutaneous treatment with LysB prevented further bacterial proliferation, associated with IFN-γ and TNF production in the draining lymph node. These findings highlight the potential use of lysins as a novel therapeutic approach against this neglected tropical disease.


Assuntos
Úlcera de Buruli/tratamento farmacológico , Endopeptidases/administração & dosagem , Micobacteriófagos/enzimologia , Mycobacterium ulcerans/efeitos dos fármacos , Animais , Bacteriólise , Úlcera de Buruli/patologia , Modelos Animais de Doenças , Endopeptidases/farmacologia , Feminino , Interferon gama/análise , Linfonodos/imunologia , Camundongos Endogâmicos BALB C , Mycobacterium ulcerans/virologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise
15.
Eur J Pharmacol ; 860: 172554, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31326378

RESUMO

Cancer treatment is one of the major fields of interest for the scientific community. Investment in cancer research is costly but essential to provide patients with more effective and safe treatments. In this project, we describe the synthesis and characterization of new thiazole derivatives coupled to CPP2, a cell-penetrating peptide (CPP) reported for colon cancer cells. Using a human adenocarcinoma-derived cell line (Caco-2), these new CPPs were evaluated for antiproliferative (3H-thymidine incorporation) and cytotoxic effect (extracellular lactate dehydrogenase activity). One of these derivatives, the BTZCA thiazole compound and its peptide-conjugated (BTZCA-CPP2) also showed the ability to decrease tumour cell viability and proliferation, with potential cytotoxic effect against human breast cancer MCF-7 cells. Then, cytotoxicity studies were developed against J774, L929 and THP1 cell lines and this new family showed no significant cytotoxicity, when compared to their counterparts alone (BTZCA and CPP2). The use of smaller CPP conjugated with this family of derivatives can be also considered in future for the development of new drugs to cancer therapy.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacologia , Sequência de Aminoácidos , Linhagem Celular Tumoral , Tamanho Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Tiazóis/química
16.
Appl Environ Microbiol ; 85(17)2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31227554

RESUMO

Acinetobacter baumannii is emerging as a major nosocomial pathogen in intensive care units. The bacterial capsules are considered major virulence factors, and the particular A. baumannii capsular type K2 has been associated with high antibiotic resistance. In this study, we identified a K2 capsule-specific depolymerase in a bacteriophage tail spike C terminus, a fragment that was heterologously expressed, and its antivirulence properties were assessed by in vivo experiments. The K2 depolymerase is active under a broad range of environmental conditions and is highly thermostable, with a melting point (Tm ) at 67°C. In the caterpillar larva model, the K2 depolymerase protects larvae from bacterial infections, using either pretreatments or with single-enzyme injection after bacterial challenge, in a dose-dependent manner. In a mouse sepsis model, a single K2 depolymerase intraperitoneal injection of 50 µg is able to protect 60% of mice from an otherwise deadly infection, with a significant reduction in the proinflammatory cytokine profile. We showed that the enzyme makes bacterial cells fully susceptible to the host complement system killing effect. Moreover, the K2 depolymerase is highly refractory to resistance development, which makes these bacteriophage-derived capsular depolymerases useful antivirulence agents against multidrug-resistant A. baumannii infections.IMPORTANCEAcinetobacter baumannii is an important nosocomial pathogen resistant to many, and sometimes all, antibiotics. The A. baumannii K2 capsular type has been associated with elevated antibiotic resistance. The capsular depolymerase characterized here fits the new trend of alternative antibacterial agents needed against multidrug-resistant pathogens. They are highly specific, stable, and refractory to resistance, as they do not kill bacteria per se; instead, they remove bacterial surface polysaccharides, which diminish the bacterial virulence and expose them to the host immune system.


Assuntos
Infecções por Acinetobacter/microbiologia , Acinetobacter baumannii/fisiologia , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Glicosídeo Hidrolases/genética , Mariposas/microbiologia , Sepse/microbiologia , Acinetobacter baumannii/genética , Animais , Proteínas de Bactérias/metabolismo , Glicosídeo Hidrolases/metabolismo , Larva/crescimento & desenvolvimento , Larva/microbiologia , Camundongos , Mariposas/crescimento & desenvolvimento
17.
Curr Issues Mol Biol ; 25: 169-198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-28875944

RESUMO

Mycobacteria are intracellular pathogens that have macrophages as their main host cells. However, macrophages are also the primary line of defense against invading microorganisms. To survive in the intracellular compartment, virulent mycobacteria have developed several strategies to modulate the activation and the effector functions of macrophages. Despite this, antigen-specific T cells develop during infection. While T cell responses are critical for protection they can also contribute to the success of mycobacteria as human pathogens, as immunopathology associated with these responses facilitates transmission. Here, we provide a brief overview of different immune-evasion strategies of mycobacteria and their impact on the protective immune response. This understanding will further our knowledge in host-pathogen interactions and may provide critical insights for the development of novel host-specific therapies.


Assuntos
Células Dendríticas/imunologia , Evasão da Resposta Imune , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Mycobacterium/imunologia , Linfócitos T/imunologia , Imunidade Adaptativa , Animais , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/microbiologia , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Macrófagos/microbiologia , Mycobacterium/crescimento & desenvolvimento , Mycobacterium/patogenicidade , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/patogenicidade , Proteínas NLR/genética , Proteínas NLR/imunologia , Fagossomos/imunologia , Transdução de Sinais , Linfócitos T/microbiologia , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia
18.
Bioorg Med Chem Lett ; 27(3): 403-405, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28057421

RESUMO

Ethionamide (ETH) is an important second-line antituberculosis drug used for the treatment of patients infected with multidrug-resistant Mycobacterium tuberculosis. Recently, we reported that the loading of ETH into thermally carbonized-porous silicon (TCPSi) nanoparticles enhanced the solubility and permeability of ETH at different pH-values and also increased its metabolization process. Based on these results, we synthesized carboxylic acid functionalized thermally hydrocarbonized porous silicon nanoparticles (UnTHCPSi NPs) conjugated with ETH and its antimicrobial effect was evaluated against Mycobacterium tuberculosis strain H37Rv. The activity of the conjugate was increased when compared to free-ETH, which suggests that the nature of the synergy between the NPs and ETH is likely due to the weakening of the bacterial cell wall that improves conjugate-penetration. These ETH-conjugated NPs have great potential in reducing dosing frequency of ETH in the treatment of multidrug-resistant tuberculosis (MDR-TB).


Assuntos
Antituberculosos/química , Etionamida/química , Nanopartículas/química , Silício/química , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Etionamida/farmacologia , Etionamida/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Tamanho da Partícula , Porosidade , Solubilidade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico
19.
PLoS Negl Trop Dis ; 10(4): e0004671, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27128681

RESUMO

INTRODUCTION: Buruli ulcer (BU) is a severe necrotizing human skin disease caused by Mycobacterium ulcerans. Clinically, presentation is a sum of these diverse pathogenic hits subjected to critical immune-regulatory mechanisms. Among them, autophagy has been demonstrated as a cellular process of critical importance. Since microtubules and dynein are affected by mycolactone, the critical pathogenic exotoxin produced by M. ulcerans, cytoskeleton-related changes might potentially impair the autophagic process and impact the risk and progression of infection. OBJECTIVE: Genetic variants in the autophagy-related genes NOD2, PARK2 and ATG16L1 has been associated with susceptibility to mycobacterial diseases. Here, we investigated their association with BU risk, its severe phenotypes and its progression to an ulcerative form. METHODS: Genetic variants were genotyped using KASPar chemistry in 208 BU patients (70.2% with an ulcerative form and 28% in severe WHO category 3 phenotype) and 300 healthy endemic controls. RESULTS: The rs1333955 SNP in PARK2 was significantly associated with increased susceptibility to BU [odds ratio (OR), 1.43; P = 0.05]. In addition, both the rs9302752 and rs2066842 SNPs in NOD2 gee significantly increased the predisposition of patients to develop category 3 (OR, 2.23; P = 0.02; and OR 12.7; P = 0.03, respectively, whereas the rs2241880 SNP in ATG16L1 was found to significantly protect patients from presenting the ulcer phenotype (OR, 0.35; P = 0.02). CONCLUSION: Our findings indicate that specific genetic variants in autophagy-related genes influence susceptibility to the development of BU and its progression to severe phenotypes.


Assuntos
Autofagia , Úlcera de Buruli/genética , Úlcera de Buruli/patologia , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno , Mycobacterium ulcerans/imunologia , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Proteínas Relacionadas à Autofagia , Úlcera de Buruli/epidemiologia , Proteínas de Transporte/genética , Criança , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Proteína Adaptadora de Sinalização NOD2/genética , Medição de Risco , Ubiquitina-Proteína Ligases/genética , Adulto Jovem
20.
PLoS Negl Trop Dis ; 9(12): e0004265, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26625302

RESUMO

Buruli Ulcer (BU) is a necrotizing skin disease caused by Mycobacterium ulcerans infection. BU is characterized by a wide range of clinical forms, including non-ulcerative cutaneous lesions that can evolve into severe ulcers if left untreated. Nevertheless, spontaneous healing has been reported to occur, although knowledge on this process is scarce both in naturally infected humans and experimental models of infection. Animal models are useful since they mimic different spectrums of human BU disease and have the potential to elucidate the pathogenic/protective pathway(s) involved in disease/healing. In this time-lapsed study, we characterized the guinea pig, an animal model of resistance to M. ulcerans, focusing on the macroscopic, microbiological and histological evolution throughout the entire experimental infectious process. Subcutaneous infection of guinea pigs with a virulent strain of M. ulcerans led to early localized swelling, which evolved into small well defined ulcers. These macroscopic observations correlated with the presence of necrosis, acute inflammatory infiltrate and an abundant bacterial load. By the end of the infectious process when ulcerative lesions healed, M. ulcerans viability decreased and the subcutaneous tissue organization returned to its normal state after a process of continuous healing characterized by tissue granulation and reepethelialization. In conclusion, we show that the experimental M. ulcerans infection of the guinea pig mimics the process of spontaneous healing described in BU patients, displaying the potential to uncover correlates of protection against BU, which can ultimately contribute to the development of new prophylactic and therapeutic strategies.


Assuntos
Úlcera de Buruli/patologia , Mycobacterium ulcerans/isolamento & purificação , Pele/microbiologia , Pele/patologia , Cicatrização , Animais , Modelos Animais de Doenças , Feminino , Cobaias , Histocitoquímica
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