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1.
Lancet Infect Dis ; 21(11): 1590-1597, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34237262

RESUMO

BACKGROUND: Trials of BCG vaccination to prevent or reduce severity of COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of the beneficial, non-specific effects of BCG come largely from data on mortality in infants and young children, and from in-vitro and animal studies, after a first BCG vaccination. We assess all-cause mortality following a large BCG revaccination trial in Malawi. METHODS: The Karonga Prevention trial was a population-based, double-blind, randomised controlled in Karonga District, northern Malawi, that enrolled participants between January, 1986, and November, 1989. The trial compared BCG (Glaxo-strain) revaccination versus placebo to prevent tuberculosis and leprosy. 46 889 individuals aged 3 months to 75 years were randomly assigned to receive BCG revaccination (n=23 528) or placebo (n=23 361). Here we report mortality since vaccination as recorded during active follow-up in northern areas of the district in 1991-94, and in a demographic surveillance follow-up in the southern area in 2002-18. 7389 individuals who received BCG (n=3746) or placebo (n=3643) lived in the northern follow-up areas, and 5616 individuals who received BCG (n=2798) or placebo (n=2818) lived in the southern area. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality. FINDINGS: Follow-up information was available for 3709 (99·0%) BCG recipients and 3612 (99·1%) placebo recipients in the northern areas, and 2449 (87·5%) BCG recipients and 2413 (85·6%) placebo recipients in the southern area. There was no difference in mortality between the BCG and placebo groups in either area, overall or by age group or sex. In the northern area, there were 129 deaths per 19 694 person-years at risk in the BCG group (6·6 deaths per 1000 person-years at risk [95% CI 5·5-7·8]) versus 133 deaths per 19 111 person-years at risk in the placebo group (7·0 deaths per 1000 person-years at risk [95% CI 5·9-8·2]; HR 0·94 [95% CI 0·74-1·20]; p=0·62). In the southern area, there were 241 deaths per 38 399 person-years at risk in the BCG group (6·3 deaths per 1000 person-years at risk [95% CI 5·5-7·1]) versus 230 deaths per 38 676 person-years at risk in the placebo group (5·9 deaths per 1000 person-years at risk [95% CI 5·2-6·8]; HR 1·06 [95% CI 0·88-1·27]; p=0·54). INTERPRETATION: We found little evidence of any beneficial effect of BCG revaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, might obscure any benefits. FUNDING: British Leprosy Relief Association (LEPRA); Wellcome Trust.


Assuntos
Vacina BCG/administração & dosagem , Imunização Secundária/estatística & dados numéricos , Mortalidade , Vacinação/métodos , Adolescente , Adulto , Idoso , Vacina BCG/imunologia , COVID-19/epidemiologia , COVID-19/imunologia , COVID-19/prevenção & controle , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Imunogenicidade da Vacina , Hanseníase/imunologia , Hanseníase/mortalidade , Hanseníase/prevenção & controle , Malaui/epidemiologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , SARS-CoV-2/imunologia , Resultado do Tratamento , Tuberculose/imunologia , Tuberculose/mortalidade , Tuberculose/prevenção & controle , Vacinação/estatística & dados numéricos , Adulto Jovem
2.
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
3.
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
4.
Int J Mycobacteriol ; 8(2): 166-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31210160

RESUMO

Background: Mycobacterium tuberculosis (M. tuberculosis) and Mycobacterium leprae (M. leprae) are morphologically, immunologically, and pathologically similar. The incidence of simultaneous tuberculosis (TB) and leprosy is still controversial. The aim of this study was to detect anti-phenolic glycolipid-I (anti-PGL-I) antibody in sera from TB patients at Dr. Hasan Sadikin Hospital Bandung, West Java, Indonesia. The aim of this study is to detect anti-phenolic glycolipid-I (anti-PGL-I) antibody in sera from TB patients at Dr. Hasan Sadikin Hospital Bandung, West Java, Indonesia. Methods: We performed a cross-sectional descriptive study with consecutive sampling from 112 TB patients clinically diagnosed by internist from the Internal Medicine Department and confirmed through bacteriological, histological, and chest radiograph examinations. The specimens were taken from the blood serum of the patient. Furthermore, the anti-PGL-I immunoglobulin (Ig) M and IgG serum level were evaluated using the enzyme-linked immunosorbent assay. Results: The mean of anti-PGL-I IgM and IgG serum levels in TB patients of this study was 34.17 ± 21.94 pg/ml and 41.44 ± 18.93 pg/ml with the mean of optical density values was 0.18 ± 0.05 and 0.26 ± 0.07. The seropositivity of anti-PGL-I in TB patients was 27.68% for IgM and 41.96% for IgG. The seropositivity of anti-PGL-I IgM and IgG level based on clinical manifestation of TB in this study from the highest to the lowest were as follows: extrapulmonary TB patients (61.29% and 59.57%), pulmonary TB patients (29.03% and 36.17%), and pulmonary with extrapulmonary TB patients (9.68% and 4.26%), respectively. Conclusion: The seropositivity of anti-PGL-I antibody in sera from TB patients in Bandung, West Java, Indonesia was 27.68% for IgM and 41.96% for IgG. Furthermore, periodic observations are needed to determine the likelihood of clinical manifestation of leprosy in TB patients.


Assuntos
Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Glicolipídeos/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Hanseníase/diagnóstico , Tuberculose/imunologia , Adolescente , Adulto , Idoso , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Indonésia/epidemiologia , Hanseníase/epidemiologia , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/complicações , Tuberculose/epidemiologia , Adulto Jovem
5.
Int J Paleopathol ; 26: 37-47, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31185376

RESUMO

OBJECTIVE: Our primary objective is to re-visit the tuberculosis and leprosy cross-immunity. hypothesis through the careful integration of immunology and paleopathology. METHODS: Using an integrated theoretical analysis that evaluates clinical literature on human innate immunological responses, paleomicrobiology, bioarchaeology, and paleopathology, we develop a multifactorial model. RESULTS: Past populations do not represent homogeneous immunological landscapes, and therefore it is likely that leprosy in Medieval Europe did not uniformly decline due to cross-immunity. CONCLUSIONS: We recommend that bioarchaeological reconstructions of past disease experience take into consideration models that include variation in immune function based on past environments and social contexts. This provides a unique opportunity to conduct comprehensive analyses on complex immunological processes. SIGNIFICANCE: Extrapolating results from experimental immunology to larger populations elucidates complexities of disease cross-immunity and highlights the importance of synthesizing archaeological, social, paleopathological and biological data as a means of understanding disease in the past. LIMITATIONS: All extrapolations from data produced from in vitro studies to past populations, using living donors, pose significant limitations where, among other factors, the full reconstruction of past environmental and social contexts can frequently be sparse or incomplete. SUGGESTIONS FOR FUTURE RESEARCH: To reduce the limitations of integrating experimental immunology with bioarchaeological reconstructions (i.e. how to use skeletal samples to reconstruct inflammatory phenotypes), we propose that osteoimmunology, or the study of the interplay between immune cells and bone cells, should be considered a vital discipline and perhaps the foundation for the expansion of paleoimmunology.


Assuntos
Alergia e Imunologia , Hanseníase/imunologia , Modelos Imunológicos , Paleopatologia , Tuberculose/imunologia , Arqueologia , Reações Cruzadas , História Medieval , Humanos , Imunidade Inata/imunologia , Tuberculose/história
6.
Microbiol Spectr ; 7(3)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31172908

RESUMO

Mycobacterium tuberculosis is an ancient master of the art of causing human disease. One important weapon within its fully loaded arsenal is the type VII secretion system. M. tuberculosis has five of them: ESAT-6 secretion systems (ESX) 1 to 5. ESX-1 has long been recognized as a major cause of attenuation of the FDA-licensed vaccine Mycobacterium bovis BCG, but its importance in disease progression and transmission has recently been elucidated in more detail. This review summarizes the recent advances in (i) the understanding of the ESX-1 structure and components, (ii) our knowledge of ESX-1's role in hijacking macrophage function to set a path for infection and dissemination, and (iii) the development of interventions that utilize ESX-1 for diagnosis, drug interventions, host-directed therapies, and vaccines.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/metabolismo , Tuberculose/imunologia , Sistemas de Secreção Tipo VII/imunologia , Sistemas de Secreção Tipo VII/metabolismo , Vacina BCG/imunologia , Sistemas de Secreção Bacterianos/metabolismo , Quimiocinas , Interações Hospedeiro-Patógeno , Humanos , Macrófagos/imunologia , Mycobacterium tuberculosis/patogenicidade , Necrose , Fagossomos , Tuberculose/diagnóstico , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle , Vacinas , Virulência
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.
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
9.
Vaccine ; 36(24): 3408-3410, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29609965

RESUMO

This article presented the World Health Organization's (WHO) recommendations on the use of on Bacille Calmette-Guérin (BCG) vaccine excerpted from the BCG vaccines: WHO position paper - February 2018 published in the Weekly Epidemiological Record [1]. This position paper replaces the 2004 WHO position paper on Bacille Calmette-Guérin (BCG) vaccine [2] and the 2007 WHO revised BCG vaccination guidelines for infants at risk for human immunodeficiency virus (HIV) infection [3]. It incorporates recent developments in the tuberculosis (TB) field, provides revised guidance on the immunization of children infected with HIV, and re-emphasizes the importance of the birth dose. This position paper also includes recommendations for the prevention of leprosy. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation tables. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of cholera vaccines were discussed by the Strategic Advisory Group of Experts (SAGE) in October 2017; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/meetings/2017/october/presentations_background_docs/en/.


Assuntos
Vacina BCG/administração & dosagem , Programas de Imunização/organização & administração , Saúde Pública/legislação & jurisprudência , Tuberculose/prevenção & controle , Vacinação/legislação & jurisprudência , Organização Mundial da Saúde/organização & administração , Adolescente , Vacina BCG/provisão & distribuição , Criança , Pré-Escolar , Infecções por HIV/prevenção & controle , Política de Saúde , Humanos , Esquemas de Imunização , Lactente , Hanseníase/prevenção & controle , Guias de Prática Clínica como Assunto , Tuberculose/imunologia , Cobertura Vacinal/organização & administração , Adulto Jovem
10.
J Immunol ; 200(4): 1434-1442, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29311364

RESUMO

IFN-stimulated gene 15 (ISG15) deficiency in humans leads to severe IFNopathies and mycobacterial disease, the latter being previously attributed to its extracellular cytokine-like activity. In this study, we demonstrate a novel role for secreted ISG15 as an IL-10 inducer, unique to primary human monocytes. A balanced ISG15-induced monocyte/IL-10 versus lymphoid/IFN-γ expression, correlating with p38 MAPK and PI3K signaling, was found using targeted in vitro and ex vivo systems analysis of human transcriptomic datasets. The specificity and MAPK/PI3K-dependence of ISG15-induced monocyte IL-10 production was confirmed in vitro using CRISPR/Cas9 knockout and pharmacological inhibitors. Moreover, this ISG15/IL-10 axis was amplified in leprosy but disrupted in human active tuberculosis (TB) patients. Importantly, ISG15 strongly correlated with inflammation and disease severity during active TB, suggesting its potential use as a biomarker, awaiting clinical validation. In conclusion, this study identifies a novel anti-inflammatory ISG15/IL-10 myeloid axis that is disrupted in active TB.


Assuntos
Citocinas/imunologia , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Tuberculose/imunologia , Ubiquitinas/imunologia , Humanos
11.
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
12.
Artigo em Inglês | MEDLINE | ID: mdl-29250493

RESUMO

Tuberculosis (TB) remains one of the most severe infectious diseases. It is still of paramount importance to establish more accurate, rapid, and efficient diagnostic methods. Since infection with Mycobacterium tuberculosis (M. tb) is largely mediated through the respiratory tract, IgA responses against mycobacterial proteins are worthy of investigation for their potential clinical utility. In this study, the IgA response targeting lipoprotein Z (LppZ) was determined by using a homemade ELISA with plasma of TB patients (N = 125), LTBI individuals (N = 92), healthy controls (HCs) (N = 165), as well as TB patients undergoing anti-TB treatment (N = 9). In parallel the antigen-specific IFN-γ release from PBMCs triggered by LppZ and M. tb-specific ESAT-6 or CFP-10 was detected by using an ELISPOT assay. It was found that the LppZ-specific IgA level was dramatically higher in TB patients than in HCs (p < 0.0001). Compared to that before anti-TB treatment, the LppZ-specific IgA level decreased substantially after 2 months of anti-TB treatment (p = 0.0297) and remained at low levels until the end of the treatment. What is more, pulmonary TB patients exhibited significantly higher LppZ-specific IgA-values than extra-pulmonary TB patients (p = 0.0296). Interestingly, the LppZ-specific IgA-values were negatively correlated to the amounts of IFN-γ released in response to LppZ with statistical significance (r = -0.5806, p = 0.0002). LppZ-specific IgA level was also higher in LTBI individuals than in HCs (p < 0.0001). Additionally there were some PPD+ HC individuals with high LppZ-specific IgA levels but the potential of this assay for identifying leaky LTBI in PPD+ HCs needs to be further investigated through follow-up studies. The sensitivity of detecting TB solely with ESAT-6 or CFP-10-specific IFN-γ release was increased by including the LppZ-specific IgA results, respectively, from 86.11 to 100% and 88.89 to 100%; the sensitivity of screening for LTBI was increased from 80.36 to 83.93% and 57.14 to 69.64%, respectively. The higher LppZ-specific IgA responses in TB and LTBI populations than in controls indicated high immunoreactivity to LppZ upon M. tb infection. Although the assay was not efficient enough for independent application in sero-diagnosis, LppZ-specific IgA might become a complementary biomarker for the improvement of TB and LTBI screening.


Assuntos
Imunoglobulina A/isolamento & purificação , Tuberculose Latente/diagnóstico , Tuberculose Latente/imunologia , Lipoproteínas/isolamento & purificação , Mycobacterium tuberculosis/imunologia , Tuberculose/diagnóstico , Tuberculose/imunologia , Adulto , Idoso , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Biomarcadores , ELISPOT/métodos , Feminino , Humanos , Imunidade Celular , Interferon gama/metabolismo , Tuberculose Latente/microbiologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Lipoproteínas/genética , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/isolamento & purificação , Sensibilidade e Especificidade , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia
13.
Eur J Med Chem ; 134: 140-146, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28411454

RESUMO

A PG-tb1 hapten from the West Beijing strains of Mycobacterium tuberculosis cell wall has been efficiently synthesized and conjugated to CRM197 in a simple way as linker-equipped carbohydrate by applying squaric acid chemistry for an original neoglycoprotein, creating a potent T-dependent conjugate vaccine. The intermediate monoester can be easily purified and the degree of incorporation can be monitored by MALDI-TOF mass spectrometry. After administered systemically in mice without any adjuvant, the conjugate induced high antigen-specific IgG levels in serum. Furthermore, following the third immunization, significant antibody titers frequently exceeding 0.8 million were observed in the sera of mice vaccinated with PG-CRM197 conjugate which showed the potential for preparation of TB vaccine.


Assuntos
Antígenos de Bactérias/uso terapêutico , Proteínas de Bactérias/uso terapêutico , Glicolipídeos/uso terapêutico , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/uso terapêutico , Tuberculose/prevenção & controle , Animais , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Feminino , Glicolipídeos/química , Glicolipídeos/imunologia , Imunização , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Camundongos , Tuberculose/sangue , Tuberculose/imunologia , Vacinas contra a Tuberculose/química , Vacinas contra a Tuberculose/imunologia
14.
Hum Vaccin Immunother ; 13(5): 1040-1050, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28059670

RESUMO

Previously we showed that 65-kDa Mycobacterium leprae heat shock protein (Hsp65) is a target for the development of a tuberculosis vaccine. Here we evaluated peripheral blood mononuclear cells (PBMC) from healthy individuals or tuberculosis patients stimulated with two forms of Hsp65 antigen, recombinant DNA that encodes Hsp65 (DNA-HSP65) or recombinant Hsp65 protein (rHsp65) in attempting to mimic a prophylactic or therapeutic study in vitro, respectively. Proliferation and cytokine-producing CD4+ or CD8+ cell were assessed by flow cytometry. The CD4+ cell proliferation from healthy individuals was stimulated by DNA-HSP65 and rHsp65, while CD8+ cell proliferation from healthy individuals or tuberculosis patients was stimulated by rHSP65. DNA-HSP65 did not improve the frequency of IFN-gamma+ cells from healthy individuals or tuberculosis patients. Furthermore, we found an increase in the frequency of IL-10-producing cells in both groups. These findings show that Hsp65 antigen activates human lymphocytes and plays an immune regulatory role that should be addressed as an additional antigen for the development of antigen-combined therapies.


Assuntos
Proteínas de Bactérias/imunologia , Chaperonina 60/imunologia , Imunidade Celular , Ativação Linfocitária , Tuberculose/imunologia , Adulto , Proteínas de Bactérias/genética , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Chaperonina 60/genética , Citotoxicidade Imunológica , Feminino , Voluntários Saudáveis , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Macrófagos Alveolares/imunologia , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Proteínas Recombinantes/imunologia , Vacinas contra a Tuberculose/imunologia , Regulação para Cima , Vacinas de DNA/farmacologia , Adulto Jovem
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 Immunoassay Immunochem ; 36(4): 420-43, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25350657

RESUMO

In this study, we estimated the CD4+, CD8+, CD3+ cell counts and the CD4/CD8 ratio among normal healthy controls (adults and children), leprosy patients (without any complications and during reactional states), TB patients (with and without HIV), and HIV-positive patients (early infection and full-blown AIDS) and correlated the changes with disease progression. In our study, it was observed that among adults, CD4+ cell counts ranged from 518-1098, CD8+ from 312-952, whereas CD4/CD8 ratio from 0.75-2.30. Among children, both CD4+ and CD8+ cells were more and the CD4/CD8 ratio varied from 0.91-3.17. With regard to leprosy patients, we observed that CD4+ and CD8+ cell counts were lower among PB (pauci-bacillary) and MB (multi-bacillary) patients. CD4/CD8 ratio was 0.99 ± 0.28 among PB patients while the ratio was lower, 0.78 ± 0.20, among MB patients. CD4+ cell counts were raised during RR (reversal reactions) and ENL (erythema nodosum leprosum) among the PB and MB patients whereas the CD8+ cell counts were lower among PB and MB patients. CD4/CD8 ratio doubled during reactional episodes of RR and ENL. Among the HIV-negative tuberculosis (TB) patients, both the CD4+ and CD8+ cell counts were found to be less and the CD4/CD8 ratio varied between 0.53-1.75. Among the HIV-positive TB patients and HIV-positive patients, both the CD4+ and CD8+ cells were very less and ratio drops significantly. In the initial stages of infection, as CD4+ counts drop, an increase in the CD8+ cell counts was observed and the ratio declines. In full-blown cases, CD4+ cell counts were very low, 3-4 to 54 cells, CD8+ cells from 12-211 and the ratio drops too low. This study is the first of its kind in this region of the country and assumes importance since no other study has reported the values of CD4+ and CD8+ T-lymphocyte counts among patients with mycobacterial diseases (leprosy and TB), HIV infections along with normal healthy individuals of the region, and correlation with clinical presentations of patients.


Assuntos
Complexo CD3/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Hanseníase/imunologia , Tuberculose/imunologia , Adolescente , Adulto , Idoso , Relação CD4-CD8 , Criança , Feminino , Voluntários Saudáveis , Humanos , Índia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Infect Immun ; 82(9): 3900-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25001602

RESUMO

Leprosy remains a major global health problem and typically occurs in regions in which tuberculosis is endemic. Vaccines are needed that protect against both infections and do so better than the suboptimal Mycobacterium bovis BCG vaccine. Here, we evaluated rBCG30, a vaccine previously demonstrated to induce protection superior to that of BCG against Mycobacterium tuberculosis and Mycobacterium bovis challenge in animal models, for efficacy against Mycobacterium leprae challenge in a murine model of leprosy. rBCG30 overexpresses the M. tuberculosis 30-kDa major secretory protein antigen 85B, which is 85% homologous with the M. leprae homolog (r30ML). Mice were sham immunized or immunized intradermally with BCG or rBCG30 and challenged 2.5 months later by injection of viable M. leprae into each hind footpad. After 7 months, vaccine efficacy was assessed by enumerating the M. leprae bacteria per footpad. Both BCG and rBCG30 induced significant protection against M. leprae challenge. In the one experiment in which a comparison between BCG and rBCG30 was feasible, rBCG30 induced significantly greater protection than did BCG. Immunization of mice with purified M. tuberculosis or M. leprae antigen 85B also induced protection against M. leprae challenge but less so than BCG or rBCG30. Notably, boosting rBCG30 with M. tuberculosis antigen 85B significantly enhanced r30ML-specific immune responses, substantially more so than boosting BCG, and significantly augmented protection against M. leprae challenge. Thus, rBCG30, a vaccine that induces improved protection against M. tuberculosis, induces cross-protection against M. leprae that is comparable or potentially superior to that induced by BCG, and boosting rBCG30 with antigen 85B further enhances immune responses and protective efficacy.


Assuntos
Aciltransferases/imunologia , Antígenos de Bactérias/imunologia , Vacina BCG/imunologia , Proteínas de Bactérias/imunologia , Proteção Cruzada/imunologia , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Feminino , Imunização/métodos , Hanseníase/imunologia , Hanseníase/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/imunologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinação/métodos
19.
Infect Immun ; 82(9): 3979-85, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25024362

RESUMO

Despite the dramatic reduction in the number of leprosy cases worldwide in the 1990s, transmission of the causative agent, Mycobacterium leprae, is still occurring, and new cases continue to appear. New strategies are required in the pursuit of leprosy elimination. The cross-application of vaccines in development for tuberculosis may lead to tools applicable to elimination of leprosy. In this report, we demonstrate that the chimeric fusion proteins ID83 and ID93, developed as antigens for tuberculosis (TB) vaccine candidates, elicited gamma interferon (IFN-γ) responses from both TB and paucibacillary (PB) leprosy patients and from healthy household contacts of multibacillary (MB) patients (HHC) but not from nonexposed healthy controls. Immunization of mice with either protein formulated with a Toll-like receptor 4 ligand (TLR4L)-containing adjuvant (glucopyranosyl lipid adjuvant in a stable emulsion [GLA-SE]) stimulated antigen-specific IFN-γ secretion from pluripotent Th1 cells. When immunized mice were experimentally infected with M. leprae, both cellular infiltration into the local lymph node and bacterial growth at the site were reduced relative to those of unimmunized mice. Thus, the use of the Mycobacterium tuberculosis candidate vaccines ID83/GLA-SE and ID93/GLA-SE may confer cross-protection against M. leprae infection. Our data suggest these vaccines could potentially be used as an additional control measure for leprosy.


Assuntos
Hanseníase/imunologia , Hanseníase/prevenção & controle , Mycobacterium leprae/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Adjuvantes Imunológicos , Animais , Antígenos de Bactérias/imunologia , Proteínas de Bactérias/imunologia , Humanos , Interferon gama/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Receptor 4 Toll-Like/imunologia
20.
Clin Infect Dis ; 58(7): e119-21, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24429428

RESUMO

Giant reactions to the tuberculin skin test are extremely rare and have been previously reported almost exclusively in patients with lepromatous leprosy. We herein report a giant tuberculin reaction associated with the homeopathic drug Tuberculinum in a patient with no evidence of active tuberculosis or leprosy.


Assuntos
Homeopatia/efeitos adversos , Teste Tuberculínico/efeitos adversos , Tuberculose/diagnóstico , Adulto , Reações Falso-Positivas , Humanos , Masculino , Controle de Qualidade , Tuberculose/imunologia
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