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1.
Sci Rep ; 10(1): 18120, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-33093532

RESUMO

Rifampicin resistance is a major therapeutic challenge, particularly in tuberculosis, leprosy, P. aeruginosa and S. aureus infections, where it develops via missense mutations in gene rpoB. Previously we have highlighted that these mutations reduce protein affinities within the RNA polymerase complex, subsequently reducing nucleic acid affinity. Here, we have used these insights to develop a computational rifampicin resistance predictor capable of identifying resistant mutations even outside the well-defined rifampicin resistance determining region (RRDR), using clinical M. tuberculosis sequencing information. Our tool successfully identified up to 90.9% of M. tuberculosis rpoB variants correctly, with sensitivity of 92.2%, specificity of 83.6% and MCC of 0.69, outperforming the current gold-standard GeneXpert-MTB/RIF. We show our model can be translated to other clinically relevant organisms: M. leprae, P. aeruginosa and S. aureus, despite weak sequence identity. Our method was implemented as an interactive tool, SUSPECT-RIF (StrUctural Susceptibility PrEdiCTion for RIFampicin), freely available at https://biosig.unimelb.edu.au/suspect_rif/ .


Assuntos
Proteínas de Bactérias/genética , Farmacorresistência Bacteriana/genética , Aprendizado de Máquina , Mutação de Sentido Incorreto , Mycobacterium leprae/genética , Mycobacterium tuberculosis/genética , Rifampina/farmacologia , Staphylococcus aureus/genética , Antituberculosos/farmacologia , Proteínas de Bactérias/química , Humanos , Hanseníase/tratamento farmacológico , Hanseníase/microbiologia , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
2.
Tuberculosis (Edinb) ; 121: 101914, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32279870

RESUMO

Mycobacteria are important causes of disease in human and animal hosts. Diseases caused by mycobacteria include leprosy, tuberculosis (TB), nontuberculous mycobacteria (NTM) infections and Buruli Ulcer. To better understand and treat mycobacterial disease, clinicians, veterinarians and scientists use a range of discipline-specific approaches to conduct basic and applied research, including conducting epidemiological surveys, patient studies, wildlife sampling, animal models, genetic studies and computational simulations. To foster the exchange of knowledge and collaboration across disciplines, the Many Hosts of Mycobacteria (MHM) conference series brings together clinical, veterinary and basic scientists who are dedicated to advancing mycobacterial disease research. Started in 2007, the MHM series recently held its 8th conference at the Albert Einstein College of Medicine (Bronx, NY). Here, we review the diseases discussed at MHM8 and summarize the presentations on research advances in leprosy, NTM and Buruli Ulcer, human and animal TB, mycobacterial disease comorbidities, mycobacterial genetics and 'omics, and animal models. A mouse models workshop, which was held immediately after MHM8, is also summarized. In addition to being a resource for those who were unable to attend MHM8, we anticipate this review will provide a benchmark to gauge the progress of future research concerning mycobacteria and their many hosts.


Assuntos
Bacteriologia , Pesquisa Biomédica , Infectologia , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium/patogenicidade , Tuberculose/microbiologia , Animais , Congressos como Assunto , Difusão de Inovações , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Mycobacterium/genética , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/epidemiologia , Tuberculose/diagnóstico , Tuberculose/epidemiologia
3.
Front Immunol ; 11: 170, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32117300

RESUMO

Diseases due to mycobacteria, including tuberculosis, leprosy, and Buruli ulcer, rank among the top causes of death and disability worldwide. Animal studies have revealed the importance of T cells in controlling these infections. However, the specific antigens recognized by T cells that confer protective immunity and their associated functions remain to be definitively established. T cells that respond to mycobacterial peptide antigens exhibit classical features of adaptive immunity and have been well-studied in humans and animal models. Recently, innate-like T cells that recognize lipid and metabolite antigens have also been implicated. Specifically, T cells that recognize mycobacterial glycolipid antigens (mycolipids) have been shown to confer protection to tuberculosis in animal models and share some biological characteristics with adaptive and innate-like T cells. Here, we review the existing data suggesting that mycolipid-specific T cells exist on a spectrum of "innateness," which will influence how they can be leveraged to develop new diagnostics and vaccines for mycobacterial diseases.


Assuntos
Antígenos de Bactérias/imunologia , Glicolipídeos/imunologia , Imunidade Inata , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/imunologia , Animais , Humanos , Memória Imunológica , Hanseníase/imunologia , Hanseníase/microbiologia , Ativação Linfocitária/imunologia , Fenótipo , Receptores de Antígenos de Linfócitos T/imunologia , Tuberculose/microbiologia
4.
Transcription ; 11(2): 53-65, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31880185

RESUMO

Recent biophysical studies of mycobacterial transcription have shed new light on this fundamental process in a group of bacteria that includes deadly pathogens such as Mycobacterium tuberculosis (Mtb), Mycobacterium abscessus (Mab), Mycobacterium leprae (Mlp), as well as the nonpathogenic Mycobacterium smegmatis (Msm). Most of the research has focused on Mtb, the causative agent of tuberculosis (TB), which remains one of the top ten causes of death globally. The enzyme RNA polymerase (RNAP) is responsible for all bacterial transcription and is a target for one of the crucial antibiotics used for TB treatment, rifampicin (Rif). Here, we summarize recent biophysical studies of mycobacterial RNAP that have advanced our understanding of the basic process of transcription, have revealed novel paradigms for regulation, and thus have provided critical information required for developing new antibiotics against this deadly disease.


Assuntos
Mycobacterium/genética , Transcrição Genética/genética , Mycobacterium/metabolismo , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , Tuberculose/microbiologia
5.
PLoS One ; 14(10): e0224239, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31648257

RESUMO

Mycobacterium indicus pranii (MIP) known for its immunotherapeutic potential against leprosy and tuberculosis is undergoing various clinical trials and also simultaneously being studied in animal models to get insight into the mechanistic details contributing to its protective efficacy as a vaccine candidate. Studies have shown potential immunomodulatory properties of MIP, the most significant being the ability to induce strong Th1 type of response, enhanced expression of pro-inflammatory cytokines, activation of APCs and lymphocytes, elicitation of M.tb specific poly-functional T cells. All of these form crucial components of host-immune response during M.tb infection. Also, MIP was found to be potent inducer of autophagy in macrophages which resulted in enhanced clearance of M.tb from MIP and M.tb co-infected cells. Hence, we further examined the component/s of MIP responsible for autophagy induction. Interestingly, we found that MIP lipids and DNA were able to induce autophagy but not the protein fraction. LAM being one of the crucial components of mycobacterial cell-wall lipids and possessing the ability of immunomodulation; we isolated LAM from MIP and did a comparative study with M.tb-LAM. Stimulation with MIP-LAM resulted in significantly high secretion of pro-inflammatory cytokines and displayed high autophagy inducing potential in macrophages as compared to M.tb-LAM. Treatment with MIP-LAM enhanced the co-localization of M.tb within the phago-lysosomes and increased the clearance of M.tb from the infected macrophages. This study describes LAM to be a crucial component of MIP which has significant contribution to its immunotherapeutic efficacy against TB.


Assuntos
Autofagia , Imunomodulação/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Macrófagos/patologia , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Animais , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Células RAW 264.7 , Tuberculose/metabolismo , Tuberculose/microbiologia
6.
Ann Hum Biol ; 46(2): 120-128, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31137975

RESUMO

Context: Tuberculosis and leprosy are readily recognised in human remains due to their typical palaeopathology. Both Mycobacterium tuberculosis (MTB) and Mycobacterium leprae (ML) are obligate pathogens and have been detected in ancient human populations. Objective: To demonstrate historical tuberculosis and leprosy cases in Europe and beyond using molecular methods, as human populations are associated with different mycobacterial genotypes. Methods: MTB and ML ancient DNA (aDNA) has been detected by DNA amplification using PCR, or by whole genome sequencing. Mycobacterial cell wall lipids also provide specific markers for identification. Results: In 18th century Hungary, the European indigenous MTB genotype 4 strains have been found. However, many individuals were co-infected with up to three MTB sub-genotypes. In 8th-14th century Europe significant differences in ML genotypes were found between northwest Europe compared with central, southern, or eastern Europe. In addition, several co-infections of MTB and ML were detected in historical samples. Conclusion: Both MTB and ML strain types differ between geographically separate populations. This is associated with ancient human migration after an evolutionary bottleneck and clonal expansion. The absence of indigenous leprosy in Europe today may be due to the greater mortality of tuberculosis in individuals who are co-infected with both organisms.


Assuntos
DNA Antigo/análise , Migração Humana/história , Hanseníase/história , Mycobacterium leprae/genética , Mycobacterium tuberculosis/genética , Tuberculose/história , Europa (Continente) , Genótipo , História do Século XVII , História do Século XVIII , História Medieval , Humanos , Hanseníase/microbiologia , Paleopatologia , Reação em Cadeia da Polimerase , Tuberculose/microbiologia , Sequenciamento Completo do Genoma
7.
Semin Immunol ; 39: 22-29, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30366662

RESUMO

Lipopolysaccharide (LPS) is a well-defined agonist of Toll-like receptor (TLR) 4 that activates innate immune responses and influences the development of the adaptive response during infection with Gram-negative bacteria. Many years ago, Dr. Edgar Ribi separated the adjuvant activity of LPS from its toxic effects, an effort that led to the development of monophosphoryl lipid A (MPL). MPL, derived from Salmonella minnesota R595, has progressed through clinical development and is now used in various product-enabling formulations to support the generation of antigen-specific responses in several commercial and preclinical vaccines. We have generated several synthetic lipid A molecules, foremost glucopyranosyl lipid adjuvant (GLA) and second-generation lipid adjuvant (SLA), and have advanced these to clinical trial for various indications. In this review we summarize the potential and current positioning of TLR4-based adjuvant formulations in approved and emerging vaccines.


Assuntos
Adjuvantes Imunológicos/farmacologia , Compostos de Alúmen/farmacologia , Glucosídeos/farmacologia , Imunogenicidade da Vacina , Lipídeo A/análogos & derivados , Tuberculose/prevenção & controle , Adjuvantes Imunológicos/química , Compostos de Alúmen/química , Animais , Glucosídeos/química , Infecções por HIV/imunologia , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Leishmaniose/imunologia , Leishmaniose/parasitologia , Leishmaniose/prevenção & controle , Hanseníase/imunologia , Hanseníase/parasitologia , Hanseníase/prevenção & controle , Lipídeo A/química , Lipídeo A/farmacologia , Lipossomos/administração & dosagem , Lipossomos/química , Lipossomos/imunologia , Malária/imunologia , Malária/parasitologia , Malária/prevenção & controle , Camundongos , Esquistossomose/imunologia , Esquistossomose/parasitologia , Esquistossomose/prevenção & controle , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/microbiologia , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Vacinas/administração & dosagem , Vacinas/química , Vacinas/imunologia
8.
mBio ; 9(5)2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30301850

RESUMO

New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection with Mycobacterium tuberculosis We report here on our work with AX-35, an arylvinylpiperazine amide, and four related analogs, which are potent antitubercular agents in vitro All five compounds showed good activity against M. tuberculosis in vitro and in infected THP-1 macrophages, while displaying only mild cytotoxicity. Isolation and characterization of M. tuberculosis-resistant mutants to the arylvinylpiperazine amide derivative AX-35 revealed mutations in the qcrB gene encoding a subunit of cytochrome bc 1 oxidase, one of two terminal oxidases of the electron transport chain. Cross-resistance studies, allelic exchange, transcriptomic analyses, and bioenergetic flux assays provided conclusive evidence that the cytochrome bc 1 -aa 3 is the target of AX-35, although the compound appears to interact differently with the quinol binding pocket compared to previous QcrB inhibitors. The transcriptomic and bioenergetic profiles of M. tuberculosis treated with AX-35 were similar to those generated by other cytochrome bc 1 oxidase inhibitors, including the compensatory role of the alternate terminal oxidase cytochrome bd in respiratory adaptation. In the absence of cytochrome bd oxidase, AX-35 was bactericidal against M. tuberculosis Finally, AX-35 and its analogs were active in an acute mouse model of TB infection, with two analogs displaying improved activity over the parent compound. Our findings will guide future lead optimization to produce a drug candidate for the treatment of TB and other mycobacterial diseases, including Buruli ulcer and leprosy.IMPORTANCE New drugs against Mycobacterium tuberculosis are urgently needed to deal with the current global TB pandemic. We report here on the discovery of a series of arylvinylpiperazine amides (AX-35 to AX-39) that represent a promising new family of compounds with potent in vitro and in vivo activities against M. tuberculosis AX compounds target the QcrB subunit of the cytochrome bc 1 terminal oxidase with a different mode of interaction compared to those of known QcrB inhibitors. This study provides the first multifaceted validation of QcrB inhibition by recombineering-mediated allelic exchange, gene expression profiling, and bioenergetic flux studies. It also provides further evidence for the compensatory role of cytochrome bd oxidase upon QcrB inhibition. In the absence of cytochrome bd oxidase, AX compounds are bactericidal, an encouraging property for future antimycobacterial drug development.


Assuntos
Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Piperazinas/farmacologia , Tuberculose/tratamento farmacológico , Amidas/farmacologia , Amidas/uso terapêutico , Animais , Linhagem Celular , Complexo III da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Tuberculose/microbiologia
9.
Mamm Genome ; 29(7-8): 523-538, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30116885

RESUMO

Mycobacterial diseases are caused by members of the genus Mycobacterium, acid-fast bacteria characterized by the presence of mycolic acids within their cell walls. Claiming almost 2 million lives every year, tuberculosis (TB) is the most common mycobacterial disease and is caused by infection with M. tuberculosis and, in rare cases, by M. bovis or M. africanum. The second and third most common mycobacterial diseases are leprosy and buruli ulcer (BU), respectively. Both diseases affect the skin and can lead to permanent sequelae and deformities. Leprosy is caused by the uncultivable M. leprae while the etiological agent of BU is the environmental bacterium M. ulcerans. After exposure to these mycobacterial species, a majority of individuals will not progress to clinical disease and, among those who do, inter-individual variability in disease manifestation and outcome can be observed. Susceptibility to mycobacterial diseases carries a human genetic component and intense efforts have been applied over the past decades to decipher the exact nature of the genetic factors controlling disease susceptibility. While for BU this search was mostly conducted on the basis of candidate genes association studies, genome-wide approaches have been widely applied for TB and leprosy. In this review, we summarize some of the findings achieved by genome-wide linkage, association and transcriptome analyses in TB disease and leprosy and the recent genetic findings for BU susceptibility.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Interações Hospedeiro-Patógeno/genética , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/microbiologia , Mycobacterium/fisiologia , Animais , Úlcera de Buruli/genética , Úlcera de Buruli/imunologia , Úlcera de Buruli/microbiologia , Ligação Genética , Estudo de Associação Genômica Ampla , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hanseníase/genética , Hanseníase/imunologia , Hanseníase/microbiologia , Infecções por Mycobacterium/imunologia , Locos de Características Quantitativas , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/microbiologia
10.
Indian J Tuberc ; 65(1): 15-22, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29332642

RESUMO

Tuberculosis (TB) is the major threat for humans from past several decades. Even after advent of several antitubercular drugs, researchers are still struggling for the mycobacterial infections in humans are TB and leprosy. Chronic infections caused by Mycobacterium tuberculosis and Mycobacterium leprae. A particular problem with both of these organisms is that they can survive inside macrophages after phagocytosis, unless these cells are activated by cytokines produced by T-lymphocytes, because of this researchers are not yet succeeded in finding effective treatment on TB. In recent years TB has spread globally and became the major issue for world healthcare organizations. Some compounds like benzothiazinones shown promising activity against mycobacterium, few compounds are in pipeline which may exhibit improved pharmacological effect. Decaprenylphosphoryl-d-ribose 2'-epimerase (DprE1) is the vulnerable target for antitubercular drug discovery. DprE1 is a flavoprotein that along with decaprenylphosphoryl-2-keto-ribose reductase catalyses epimerization of decaprenylphosphoryl-d-ribose to decaprenylphosphoryl-d-arabinose through an intermediate formation of decaprenylphosphoryl-2-keto-ribose. This conversion makes DprE1 a potential drug target. Further research requires to tackle the biggest hurdles in Tuberculosis treatment, i.e. multi drug and extensively drug resistance.


Assuntos
Antituberculosos/farmacologia , Descoberta de Drogas/métodos , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/microbiologia
11.
J Infect Public Health ; 11(4): 581-583, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29279264

RESUMO

BACKGROUND: The comprehensive epidemiology of mycobacterial disorders is scarce from our country. The incidence of Tuberculosis (TB) and Leprosy in a cohort of military personnel followed for a long duration was evaluated in this study. METHODS: The data for this descriptive epidemiologic study was derived from the electronic medical records (EMR) data of the service personnel enrolled between 1990 and 2015. They were recruited between the ages of 17 and 18 years in good health and their morbidity data was derived from the medical records. The incidence rate (IR) was calculated as per person-years (py) using appropriate statistical methods. RESULTS: The study population includes 51,217 participants (median age 33 years, range 17-54) with a mean follow up of 12.5 years. Yearly evaluation of the data gave a cumulative follow up duration of 613,925py. A total of 530 patients developed TB, giving an IR of 86.3 per 100,000 person years (95% CI 79.2-93.9). Leprosy was diagnosed in 59 cases giving an IR of 9.6 per 100,000py (95% CI 7.4-12.3). Pulmonary (71%) and pleural (24%) locations were the most common sites of the TB infection. The data about the contribution of the mycobacterial disorders towards the mortality and the subtypes of leprosy was not available in the EMR. CONCLUSION: Low IR of mycobacterial disorders was observed in this study when compared with the previous reports. Healthy lifestyle and good socioeconomic status could explain the low IR of mycobacterial disorders in the military personnel.


Assuntos
Hanseníase/epidemiologia , Militares/estatística & dados numéricos , Tuberculose/epidemiologia , Adolescente , Adulto , Estudos de Coortes , Registros Eletrônicos de Saúde , Humanos , Incidência , Índia/epidemiologia , Tuberculose Latente/epidemiologia , Hanseníase/diagnóstico , Hanseníase/microbiologia , Pulmão/microbiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium/isolamento & purificação , Pleura/microbiologia , Prevalência , Fatores de Risco , Fatores de Tempo , Tuberculose/diagnóstico , Tuberculose/microbiologia , Adulto Jovem
12.
Infect Genet Evol ; 66: 361-375, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-28843547

RESUMO

An arms race is an appropriate metaphor to use for the interaction of man and Mycobacterium tuberculosis (M.tb) through the millennia. Estimates of the time of infection of modern humans with M.tb often pre-date the Out-of-Africa migration. Humans have adapted to the changing environment during the migration with respect to climate, food sources and encounters with local pathogens. More recently, there has been adaptation to the demographic changes brought about in the majority of the human population by the Neolithic revolution. By chance and/or selection, specific variants in immune defence have arisen in different population groups. These select for M.tb strains more fit to cause disease and be transmitted, sometimes by exploiting defence systems effective on other bacteria. The different selection pressures on the M.tb lineages carried by specific human groups have resulted in a worldwide M.tb population that is geographically structured according to the humans historically found there. A similar structure is seen with pathogens such as M. leprae and Helicobacter pylori. Modern M.tb strains have emerged which may be more fit, such as the Beijing lineage, leading to their rapid spread both in the areas where they arose, and into new areas after recent introduction. The speed at which this is occurring is outpacing coevolution for the time being. By using the results of genome wide and other association studies, as well as admixture mapping and 'natural experiments' in areas where both a number of populations, admixed populations, and a variety of M.tb strains occur, we can investigate the forces that have driven the coevolution of man and M.tb. The diversity of human and bacterial genetic background may be used in the future to discover and target the specific host-pathogen interactions leading to tuberculosis diseases, which suggests the potential for rational design of vaccines and host-directed therapies.


Assuntos
Evolução Biológica , Interações Hospedeiro-Patógeno , Mycobacterium tuberculosis/fisiologia , Tuberculose/microbiologia , Animais , Demografia , Suscetibilidade a Doenças , Meio Ambiente , Saúde Global , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Migração Humana , Humanos , Tuberculose/epidemiologia , Tuberculose/genética , Tuberculose/imunologia
13.
Am J Phys Anthropol ; 162(1): 143-156, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27704524

RESUMO

It is possible that during long lasting chronic infections such as tuberculosis (TB) and leprosy individuals who generate a stronger immune response will produce a chronic shift in the systemic levels of inflammatory proteins. Consequently, the systemic immunological shift could affect inflammatory responses against other persistent pathogens such as Porphyromonas gingivalis associated with periodontal disease (PD). OBJECTIVE: To determine if in vitro exposure to Mycobacterium tuberculosis or M. leprae lysates impacts subsequent immune responses to P. gingivalis; and to propose a new dialogue between experimental immunology and paleopathology. MATERIAL AND METHODS: We sequentially (2 days protocol) exposed peripheral blood mononuclear cells (PBMCs) from healthy donors to bacterial lysates either from M. tuberculosis, or M. leprae, or P. gingivalis. After collecting all supernatants, we measured the expression of immune proteins TNFα and IFNγ using an enzyme-linked immunosorbent assay. RESULTS: Early exposure (day 1) of PBMCs to M. leprae or M. tuberculosis lysates induces an inflammatory shift detected by the increase of TNFα and IFNγ when the same cells are subsequently (day 2) exposed to oral pathogen P. gingivalis. DISCUSSION: By extrapolating these results, we suggest that chronic infections, such as TB and leprosy, could generate a systemic immunological shift that can affect other inflammatory processes such the one present in PD. We propose that the presence and severity of PD should be explored as a proxy for inflammatory status or competence when reconstructing the health profile in past populations.


Assuntos
Inflamação/imunologia , Inflamação/microbiologia , Hanseníase/microbiologia , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/microbiologia , Arqueologia , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Leucócitos Mononucleares , Mycobacterium leprae/metabolismo , Mycobacterium tuberculosis/metabolismo , Porphyromonas gingivalis/imunologia
14.
J Microbiol Methods ; 127: 24-27, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27164021

RESUMO

Attempts were made to enhance the sensitivity of immuno-PCR assay based on the detection of cocktail of mycobacterial antigen 85B (Rv1886c), ESAT-6 (Rv3875) and cord factor (trehalose 6,6'-dimycolate) in pulmonary and extrapulmonary TB patients. Detection of Ag85B was found to be superior to the detection of cocktail in TB patients.


Assuntos
Antígenos de Bactérias/análise , Fatores Corda/análise , Reação em Cadeia da Polimerase/métodos , Tuberculose/diagnóstico , Antígenos de Bactérias/imunologia , Fatores Corda/imunologia , Imunoensaio/métodos , Tuberculose/microbiologia , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/microbiologia
15.
PLoS Negl Trop Dis ; 10(5): e0004701, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27192147

RESUMO

Epidemiological differences exist between Mycobacterium africanum (Maf)- and Mycobacterium tuberculosis (Mtb)-infected patients, but to date, contributing host factors have not been characterised. We analysed clinical outcomes, as well as soluble markers and gene expression profiles in unstimulated, and ESAT6/CFP-10-, whole-Maf- and Mtb-stimulated blood samples of 26 Maf- and 49 Mtb-HIV-negative tuberculosis patients before, and after 2 and 6 months of anti-tuberculosis therapy. Before treatment, both groups had similar clinical parameters, but differed in few cytokines concentration and gene expression profiles. Following treatment the body mass index, skinfold thickness and chest X-ray scores showed greater improvement in the Mtb- compared to Maf-infected patients, after adjusting for age, sex and ethnicity (p = 0.02; 0.04 and 0.007, respectively). In addition, in unstimulated blood, IL-12p70, IL12A and TLR9 were significantly higher in Maf-infected patients, while IL-15, IL-8 and MIP-1α were higher in Mtb-infected patients. Overnight stimulation with ESAT-6/CFP-10 induced significantly higher levels of IFN-γ and TNF-α production, as well as gene expression of CCL4, IL1B and TLR4 in Mtb- compared to Maf-infected patients. Our study confirms differences in clinical features and immune genes expression and concentration of proteins associated with inflammatory processes between Mtb- and Maf-infected patients following anti-tuberculosis treatment These findings have public health implications for treatment regimens, and biomarkers for tuberculosis diagnosis and susceptibility.


Assuntos
Antituberculosos/uso terapêutico , Citocinas/sangue , Mycobacterium tuberculosis/imunologia , Mycobacterium/imunologia , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Adolescente , Adulto , Idoso , Antígenos de Bactérias/imunologia , Biomarcadores/sangue , Feminino , Gâmbia , Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/sangue , Interleucina-5/sangue , Interleucina-8/sangue , Masculino , Pessoa de Meia-Idade , Mycobacterium/efeitos dos fármacos , Mycobacterium/isolamento & purificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/etnologia , Tuberculose/microbiologia , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Adulto Jovem
16.
J Infect Dis ; 213 Suppl 2: S41-6, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-27025697

RESUMO

BACKGROUND: Diagnosis of multidrug-resistant tuberculosis and prompt initiation of effective treatment rely on access to rapid and reliable drug-susceptibility testing. Efficient specimen transport systems and appropriate training on specimen referral contribute to optimal and timely access to tuberculosis diagnostic services. METHODS: With support and technical assistance from a public-private partnership (PPP) between Becton Dickinson and the US President's Emergency Plan for AIDS Relief, the Uganda National TB Reference Laboratory (NTRL) and National TB and Leprosy Program redesigned the tuberculosis specimen transport network and trained healthcare workers with the goal of improving multidrug-resistant tuberculosis detection. RESULTS: Between 2008 and 2011, the PPP mapped 93% of health facilities and trained 724 healthcare and postal staff members covering 72% of districts. Strengthening the tuberculosis specimen referral system increased referrals from presumptive multidrug-resistant tuberculosis cases by >10-fold, with 94% of specimens reaching the NTRL within the established target transport time. CONCLUSIONS: This study demonstrates the potential of PPP collaborations with ministries of health to positively influence patient care by strengthening laboratory systems through increased access to drug-susceptibility testing in Uganda. Ongoing efforts to integrate specimen transport networks will maximize resources and improve patient management.


Assuntos
Instalações de Saúde , Laboratórios/organização & administração , Mycobacterium tuberculosis/isolamento & purificação , Parcerias Público-Privadas , Manejo de Espécimes , Tuberculose/diagnóstico , Atenção à Saúde/organização & administração , Pessoal de Saúde/educação , Necessidades e Demandas de Serviços de Saúde , Humanos , Laboratórios/normas , Testes de Sensibilidade Microbiana , Programas Nacionais de Saúde , Encaminhamento e Consulta , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Uganda
17.
J Trop Pediatr ; 62(2): 131-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26705331

RESUMO

BACKGROUND: : Treatment outcomes of tuberculosis (TB) in children are rarely evaluated by most national TB programmes in sub-Saharan Africa. This study evaluated the treatment outcomes of children treated for TB in Lagos State, Nigeria. METHODS: A retrospective review of programme data of the Lagos state TB and the Leprosy control programme in Nigeria from 1 January 2012 to 31 December 2012. Treatment outcomes were categorized according to the national TB guidelines. RESULTS: A total of 535 cases of childhood TB were notified in 2012, representing 6.3% of the total TB cases notified in Lagos state in 2012. The prevalence of TB/HIV co-infection was 29%. The treatment success rate was 79.2% in TB/HIV-negative children compared with 73.4% in TB/HIV-positive children (p = 0.1268). Children <1 year had the worst treatment outcomes (p < 0.001). CONCLUSION: There is a need to intensify effort at improving notification and treatment outcomes in children.


Assuntos
Antituberculosos/uso terapêutico , Coinfecção , Notificação de Doenças/estatística & dados numéricos , Infecções por HIV/complicações , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/tratamento farmacológico , Infecções Oportunistas Relacionadas com a AIDS/complicações , Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Infecções Oportunistas Relacionadas com a AIDS/epidemiologia , Adolescente , Criança , Pré-Escolar , Coinfecção/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Nigéria/epidemiologia , Vigilância da População , Prevalência , Estudos Retrospectivos , Escarro/microbiologia , Resultado do Tratamento , Tuberculose/diagnóstico , Tuberculose/epidemiologia , Tuberculose/microbiologia
18.
Crit Rev Microbiol ; 42(5): 738-58, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26089025

RESUMO

The method of genotyping by variable number tandem repeats (VNTRs) facilitates the epidemiological studies of different Mycobacterium species worldwide. Until now, the VNTR method is not fully understood, for example, its discovery, function and classification. The inconsistent nomenclature and terminology of VNTR is especially confusing. In this review, we first describe in detail the VNTRs in Mycobacterium tuberculosis (M. tuberculosis), as this pathogen resulted in more deaths than any other microbial pathogen as well as for which extensive studies of VNTRs were carried out, and then we outline the recent progress of the VNTR-related epidemiological research in several other Mycobacterium species, such as M. abscessus, M. africanum, M. avium, M. bovis, M. canettii, M. caprae, M. intracellulare, M. leprae, M. marinum, M. microti, M. pinnipedii and M. ulcerans from different countries and regions. This article is aimed mainly at the practical notes of VNTR to help the scientists in better understanding and performing this method.


Assuntos
Técnicas de Tipagem Bacteriana/métodos , Repetições Minissatélites , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/microbiologia , Animais , Genótipo , Humanos , Mycobacterium tuberculosis/classificação , Mycobacterium tuberculosis/metabolismo
19.
Eur J Clin Microbiol Infect Dis ; 34(9): 1733-49, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26210385

RESUMO

Humans have evolved alongside infectious diseases for millennia. Despite the efforts to reduce their incidence, infectious diseases still pose a tremendous threat to the world population. Fast development of molecular techniques and increasing risk of new epidemics have resulted in several studies that look to the past in order to investigate the origin and evolution of infectious diseases. Tuberculosis and leprosy have become frequent targets of such studies, owing to the persistence of their molecular biomarkers in ancient material and the characteristic skeletal lesions each disease may cause. This review examines the molecular methods used to screen for the presence of M. tuberculosis and M. leprae ancient DNA (aDNA) and their differentiation in ancient human remains. Examples of recent studies, mainly from Europe, that employ the newest techniques of molecular analysis are also described. Moreover, we present a specific approach based on assessing the likely immunological profile of historic populations, in order to further elucidate the influence of M. tuberculosis and M. leprae on historical human populations.


Assuntos
Genoma Bacteriano/genética , Hanseníase/diagnóstico , Mycobacterium leprae/genética , Mycobacterium tuberculosis/genética , Tuberculose/diagnóstico , Arqueologia , Evolução Biológica , DNA Bacteriano/genética , Europa (Continente) , Predisposição Genética para Doença , Humanos , Hanseníase/microbiologia , Tipagem Molecular/métodos , Tuberculose/microbiologia
20.
Expert Opin Ther Pat ; 25(6): 729-35, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25752488

RESUMO

Tuberculosis is one of the main causes of mortality with 1.5 million deaths a year worldwide. The growing emergence of multi- and extremely resistant strains highlights the urgent need of novel antibiotic strategies. Ethionamide, interfering with the mycobacterial membrane biosynthesis, is used in second-line treatment. This molecule is a prodrug, which requires activation by EthA. The patent described in this evaluation (WO2014049107A1) claimed a new family of molecules and their use as antibiotic treatment against mycobacteria such as Mycobacterium tuberculosis, M. leprae and atypical mycobacteria, either as a single active agent or in combination with antibiotics activable by EthA pathway.


Assuntos
Antituberculosos/uso terapêutico , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Antituberculosos/administração & dosagem , Antituberculosos/farmacologia , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Humanos , Infecções por Mycobacterium/tratamento farmacológico , Infecções por Mycobacterium/microbiologia , Mycobacterium tuberculosis/isolamento & purificação , Patentes como Assunto , Pró-Fármacos , Tuberculose/epidemiologia , Tuberculose/microbiologia
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