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1.
Scand J Immunol ; 93(5): e13010, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33325540

RESUMO

World Health Organisation recommends the practice of BCG vaccination at birth in countries which have a high incidence of tuberculosis and/or high leprosy burden. The BCG vaccination is considered safe for a competent immune system. However, in children with weakened immune systems cause of which can be primary or secondary, the vaccine may lead to side effects which can be localized or disseminated. In this study, we report a spectrum of inborn errors of immunity (IEI) commonly referred to as primary immunodeficiency disorders (PIDs) diagnosed in a large cohort of patients presenting with complications to BCG vaccination from India. Retrospective data analysis of patients referred to ICMR- National Institute of Immunohematology (ICMR-NIIH) for IEI workup between 2007 and 2019 was done. IEI was identified in n = 52/90 (57.7%) patients presenting with BCG complications. Of these, n = 13(14.4%) patients were diagnosed with severe combined immune deficiency, n = 15(16.7%) with chronic granulomatous disease, n = 19(21.1%) with Inborn errors of IFN-γ immunity, n = 4(4.4%) with Combined immunodeficiency and n = 1(1.1%) with Leucocyte Adhesion Deficiency type1. Majority of cases with BCGosis (88%) had an underlying IEI. This study strongly highlights the need for evaluation of patients with BCG complications for underlying IEI. While disseminated BCGosis strongly predicts underlying IEI, even localized persistent adenitis may be a warning sign of underlying IEI. It is also strongly recommended to record a family history of previous sibling death prior to administration of this live vaccine and deferring live vaccine till the diagnosis of IEI is ruled out in cases with a positive family history.


Assuntos
Vacina BCG/efeitos adversos , Doença Granulomatosa Crônica/patologia , Imunodeficiência Combinada Severa/patologia , Tuberculose Pulmonar/prevenção & controle , Vacinação/efeitos adversos , Vacina BCG/imunologia , Feminino , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/imunologia , Humanos , Índia , Lactente , Masculino , Mycobacterium tuberculosis/imunologia , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/imunologia , Resultado do Tratamento
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
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.
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
7.
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
8.
Front Immunol ; 9: 308, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29535713

RESUMO

Tuberculosis (TB) and leprosy still represent significant public health challenges, especially in low- and lower middle-income countries. Both poverty-related mycobacterial diseases require better tools to improve disease control. For leprosy, there has been an increased emphasis on developing tools for improved detection of infection and early diagnosis of disease. For TB, there has been a similar emphasis on such diagnostic tests, while increased research efforts have also focused on the development of new vaccines. Bacille Calmette-Guérin (BCG), the only available TB vaccine, provides insufficient and inconsistent protection to pulmonary TB in adults. The impact of BCG on leprosy, however, is significant, and the introduction of new TB vaccines that might replace BCG could, therefore, have serious impact also on leprosy. Given the similarities in antigenic makeup between the pathogens Mycobacterium tuberculosis (Mtb) and M. leprae, it is well possible, however, that new TB vaccines could cross-protect against leprosy. New TB subunit vaccines currently evaluated in human phase I and II studies indeed often contain antigens with homologs in M. leprae. In this review, we discuss pre-clinical studies and clinical trials of subunit or whole mycobacterial vaccines for TB and leprosy and reflect on the development of vaccines that could provide protection against both diseases. Furthermore, we provide the first preclinical evidence of such cross-protection by Mtb antigen 85B (Ag85B)-early secretory antigenic target (ESAT6) fusion recombinant proteins in in vivo mouse models of Mtb and M. leprae infection. We propose that preclinical integration and harmonization of TB and leprosy research should be considered and included in global strategies with respect to cross-protective vaccine research and development.


Assuntos
Antígenos de Bactérias/imunologia , Hanseníase , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose , Tuberculose Pulmonar , Animais , Proteínas de Bactérias/imunologia , Proteção Cruzada , Modelos Animais de Doenças , Humanos , Hanseníase/imunologia , Hanseníase/prevenção & controle , Camundongos , Vacinas contra a Tuberculose/imunologia , Vacinas contra a Tuberculose/uso terapêutico , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/prevenção & controle
9.
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
10.
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
11.
Diagn Microbiol Infect Dis ; 87(4): 328-334, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28126361

RESUMO

To advance toward a whole blood assay (WBA)-based test capable of facilitating the diagnosis of paucibacillary (PB) leprosy, we evaluated a prototype in-tube WBA using combinations of Mycobacterium leprae antigens. Blood was collected from newly diagnosed untreated PB (n=38), multibacillary (MB) (n=30), healthy household contacts (HHC) of MB (n=27), and endemic controls (n=61) residing in Goiânia and Fortaleza, Brazil. Blood was incubated with M. leprae cell sonicate, recombinant proteins (46f+LID-1; ML0276+LID-1), or controls (phosphate-buffered saline, phytohemagglutinin, M. tuberculosis purified protein derivative). Antigen-specific IFNγ production was observed in 71-84% and 55% of PB and HHC, respectively. Antigen-specific CXCL10 levels were similarly assessed to determine if, unlike IFNγ, CXCL10 could differentiate PB from HHC with repeated exposure/asymptomatic M. leprae infection. The CXCL10 levels induced in response to M. leprae antigens could not, however, differentiate PB from HHC. Despite these limitations, the WBAs reported here still represent important tools for assessing M. leprae infection rates and evaluating the impact of control measures.


Assuntos
Antígenos de Bactérias/imunologia , Infecções Assintomáticas/epidemiologia , Quimiocina CXCL10/imunologia , Interferon gama/imunologia , Hanseníase Paucibacilar/imunologia , Hanseníase Paucibacilar/microbiologia , Mycobacterium leprae/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/imunologia , Bioensaio/métodos , Brasil , Feminino , Humanos , Hanseníase Paucibacilar/sangue , Hanseníase Paucibacilar/diagnóstico , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis/imunologia , Proteínas Recombinantes/imunologia , Adulto Jovem
12.
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
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.
Tuberculosis (Edinb) ; 101S: S99-S104, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27742462

RESUMO

Mycobacterium tuberculosis secretes a number of proteins into the extracellular milieu during growth. Several of these proteins have been associated with modulation of the host immune response. Antigen 84, or Wag31, is one such protein that is conserved among all mycobacterial species and is recognized by the sera from tuberculosis and leprosy patients. Here, we examined the effect of Wag31 on the ability of activated human T cells to produce cytokines such as IL-10, IL-17 and IFN-γ in response to combined anti-CD3 and anti-CD28 stimulation. Purified recombinant Wag31 inhibited the secretion of IL-10 and IL-17, but not IFN-γ, by human T cells stimulated with plate-bound anti-CD3 and anti-CD28 monoclonal antibodies. Furthermore, the C-terminal domain, but not the N-terminal domain, inhibited the production of IL-10 and IL-17 without a significant effect on the production of IFN-γ. These data suggest that Wag31 may modulate human T cell immune responses during tuberculosis infection through its C-terminal domain.


Assuntos
Proteínas de Bactérias/farmacologia , Citocinas/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Linfócitos T/efeitos dos fármacos , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Células Cultivadas , Citocinas/imunologia , Relação Dose-Resposta a Droga , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Domínios Proteicos , Relação Estrutura-Atividade , Linfócitos T/imunologia , Linfócitos T/metabolismo
15.
Tuberculosis (Edinb) ; 100: 82-88, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27553414

RESUMO

Cell wall components are major determinants of virulence of Mycobacterium tuberculosis and they contribute to the induction of both humoral and cell-mediated immune response. The mammalian cell entry protein 1A (Mce1A), in the cell wall of M. tuberculosis, mediates entry of the pathogen into mammalian cells. Here, we examined serum immunoglobulin levels (IgA, IgM and total IgG) against Mce1A as a potential biomarker for diagnosis and monitoring tuberculosis (TB) treatment response. Serum samples of 39 pulmonary TB patients and 65 controls (15 healthy household contacts, 19 latently infected household contacts, 13 non-TB and 18 leprosy patients) were screened by ELISA. The median levels of all immunoglobulin classes were significantly higher in TB patients when compared with control groups. The positive test results for IgA, IgM and total IgG were 62, 54 and 82%, respectively. For comparison, routine sputum smear examination diagnosed only 26 (67%) of 39 TB cases. Sensitivities of IgA, IgM and IgG test were 59, 51.3 and 79.5%, respectively, while the specificities observed were 77.3, 83.3 and 84.4%, respectively. A significant decrease compared with baseline was also shown after TB treatment. These results suggest that circulating total IgG antibody to Mce1A could be a complementary tool to diagnosis pulmonary TB.


Assuntos
Anticorpos Antibacterianos/biossíntese , Proteínas de Bactérias/imunologia , Imunoglobulina G/biossíntese , Mycobacterium tuberculosis/imunologia , Tuberculose Pulmonar/diagnóstico , Adolescente , Adulto , Antituberculosos/uso terapêutico , Biomarcadores/sangue , Criança , Diagnóstico Diferencial , Monitoramento de Medicamentos/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Hanseníase/diagnóstico , Hanseníase/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sensibilidade e Especificidade , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/transmissão , Adulto Jovem
16.
Microbiol Spectr ; 4(3)2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27337485

RESUMO

The key question our work has sought to address has been, "What are the necessary and sufficient conditions that engender protection from intracellular pathogens in the human host?" The origins of this work derive from a long-standing interest in the mechanisms of protection against two such paradigmatic intracellular pathogens, Mycobacterium tuberculosis and Mycobacterium leprae, that have brilliantly adapted to the human host. It was obvious that these pathogens, which cause chronic diseases and persist in macrophages, must have acquired subtle strategies to resist host microbicidal mechanisms, yet since the vast majority of individuals infected with M. tuberculosis do not develop disease, there must be some potent human antimicrobial mechanisms. What follows is not a comprehensive review of the vast literature on the role of human macrophages in protection against infectious disease, but a summary of the research in our two laboratories with collaborators that we hope has contributed to some understanding of mechanisms of resistance and pathogenesis. While mouse models revealed some necessary conditions for protection, e.g., innate immunity, Th1 cells and their cytokines, and major histocompatibility complex class I-restricted T cells, here we emphasize multiple antimicrobial mechanisms that exist in human macrophages that differ from those of most experimental animals. Prominent here is the vitamin D-dependent antimicrobial pathway common to human macrophages activated by innate and acquired immune responses, mediated by antimicrobial peptides, e.g., cathelicidin, through an interleukin-15- and interleukin-32-dependent common pathway that is necessary for macrophage killing of M. tuberculosis in vitro.


Assuntos
Interações Hospedeiro-Patógeno , Macrófagos/imunologia , Macrófagos/microbiologia , Mycobacterium leprae/crescimento & desenvolvimento , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Animais , Resistência à Doença , Humanos
17.
PLoS Pathog ; 12(6): e1005705, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27355424

RESUMO

Triggering antimicrobial mechanisms in macrophages infected with intracellular pathogens, such as mycobacteria, is critical to host defense against the infection. To uncover the unique and shared antimicrobial networks induced by the innate and adaptive immune systems, gene expression profiles generated by RNA sequencing (RNAseq) from human monocyte-derived macrophages (MDMs) activated with TLR2/1 ligand (TLR2/1L) or IFN-γ were analyzed. Weighed gene correlation network analysis identified modules of genes strongly correlated with TLR2/1L or IFN-γ that were linked by the "defense response" gene ontology term. The common TLR2/1L and IFN-γ inducible human macrophage host defense network contained 16 antimicrobial response genes, including S100A12, which was one of the most highly induced genes by TLR2/1L. There is limited information on the role of S100A12 in infectious disease, leading us to test the hypothesis that S100A12 contributes to host defense against mycobacterial infection in humans. We show that S100A12 is sufficient to directly kill Mycobacterium tuberculosis and Mycobacterium leprae. We also demonstrate that S100A12 is required for TLR2/1L and IFN-γ induced antimicrobial activity against M. leprae in infected macrophages. At the site of disease in leprosy, we found that S100A12 was more strongly expressed in skin lesions from tuberculoid leprosy (T-lep), the self-limiting form of the disease, compared to lepromatous leprosy (L-lep), the progressive form of the disease. These data suggest that S100A12 is part of an innate and adaptive inducible antimicrobial network that contributes to host defense against mycobacteria in infected macrophages.


Assuntos
Hanseníase/imunologia , Macrófagos/imunologia , Proteína S100A12/imunologia , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Macrófagos/microbiologia , Infecções por Mycobacterium/imunologia , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
18.
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
19.
Sci Rep ; 6: 21780, 2016 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-26908331

RESUMO

Antigen presenting cells (APC) are critical components of innate immunity and consequently shape the adaptive response. Leukocyte Ig Like Receptors (LILR) are innate immune receptors predominantly expressed on myeloid cells. LILR can influence the antigen presenting phenotype of monocytic cells to determine the nature of T cell responses in infections including Mycobaterium leprae. We therefore investigated the relevance of LILR in the context of Mycobacterium tuberculosis. Real-time PCR studies indicated that the transcriptional profile of the orphan receptor LILRB5 was significantly up-regulated following exposure to mycobacteria. Furthermore, LILRA1 and LILRB5 were able to trigger signalling through direct engagement of mycobacteria using tranfectant cells incorporating a reporter system. We describe for the first time the expression of this receptor on T cells, and highlight the potential relevance to mycobacterial recognition. Furthermore, we demonstrate that crosslinking of this receptor on T cells increases proliferation of cytotoxic, but not helper, T cells.


Assuntos
Antígenos CD/metabolismo , Receptores Imunológicos/metabolismo , Antígenos CD/genética , Vacina BCG/imunologia , Proliferação de Células , Células Cultivadas , Células Dendríticas/metabolismo , Expressão Gênica , Humanos , Imunidade Inata , Mycobacterium tuberculosis/imunologia , Receptores Imunológicos/genética , Linfócitos T/metabolismo , Vacinação
20.
Clin Infect Dis ; 61(9): 1439-40, 2015 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-26209684

RESUMO

Five of 10 paucibacillary leprosy patients were Quantiferon Gold (Q-G) positive with negative chest X-rays. Forty multibacillary leprosy patients were negative. Reports have shown 100% cross-reactivity of ESAT6 and CFP10 between Mycobacterium leprae and Mycobacterium tuberculosis. The Q-G test cannot detect latent tuberculosis in patients with leprosy.


Assuntos
Erros de Diagnóstico , Testes de Liberação de Interferon-gama/métodos , Tuberculose Latente/diagnóstico , Hanseníase/complicações , Antígenos de Bactérias/imunologia , Reações Cruzadas , Humanos , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia
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