2010 Annual Report
NATIONAL INSTITUTE OF SCIENCE AND TECHNOLOGY IN TROPICAL DISEASES (INCT-DT)
Annual Activity Report
Period: 2/4/2009 – 2/4/2010
Coordinator: Edgar M. Carvalho
1. Introduction
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The National Institute of Science and Technology in Tropical Diseases (INCT-DT) is comprised of outstanding researchers with the goal of advancing scientific knowledge in the areas of molecular biology, genetics and immunology in leishmaniasis, Chagas disease, schistosomiasis, leprosy, tuberculosis and HTLV-1infection in order to reduce the impact of these neglected diseases on vulnerable populations. The Institute's mission is to train people in the science and technology necessary to develop research activities that work towards the ultimate control and alleviation of these diseases. The INCT-DT is composed of researchers from the Faculty of Medicine of the Federal University of Bahia, The Institute of Health Sciences of the Federal University of Bahia (ICS), the Department of Biochemistry of the Federal University of Rio Grande do Norte (UFRN), the Gonçalo Moniz Research Center - Fiocruz Bahia (CPGM - Fiocruz), the René Rachou Research Center - Fiocruz-Minas Gerais (CPqRR-Fiocruz) and The Federal University of Minas Gerais (UFMG).The headquarters of the INCT-DT is the Immunology Service (SIM) of the University Hospital Professor Edgard Santos, Federal University of Bahia, an institution nationally and internationally recognized as a center of excellence in the study of tropical diseases.
In the area of clinical research, the Institute's program aims to:
1) identify mechanisms related to the pathogenesis of tropical diseases, 2) identify markers of clinical evolution and therapeutic response, and 3) develop new strategies for treatment and control tropical diseases.
In terms of contributions to society at large, the INC-DT proposes to increase community awareness about these neglected diseases, create more spaces for students to conduct scientific research before graduate school as well as to create more opportunities for graduate and post-doctoral students with training focused on applied research. The scientific projects proposed by INCT-DT are grouped into five main areas of research:
1) Immunopathogenesis, immunodiagnosis and immunotherapy of leishmaniasis; 2) Biological markers of disease expression in T. cruzi infection; 3) biomarkers and immunotherapy in HTLV-1 infection; 4) Immunogenetics of leprosy; 5) Markers of protection and pathogenesis in schistosomiasis.
The goals of these respective areas will be realized in three time frames:
1) Short term: immunological identification of biomarkers of disease and resistance, 2) Intermediate: identification of genetic biomarkers of disease and resistance, and test effectiveness of alternative therapies, 3) Long term: identification of antigens with potential immunotherapeutic or prophylactic. |
2. Manager Committee
| The manager Committee is composed by Dr. Edgar M. Carvalho, Coordinator, University Federal of Bahia (UFBA), Dr. Selma Jerônimo, Vice-coordinator, University of Rio Grande do Norte (UFRN), Dr. Walderez Dutra (UFMG), Dr. Songeli Freire Menezes (ICS-UFBA), Dr. Rodrigo Correa-Oliveira (Fiocruz-MG) and Dr. Maria Ilma Araújo (SIM-UFBA). The committee met up on three opportunities in the year 2009-2010. On these occasions they discussed and implemented measures that allowed quicker and lower costs for acquiring imported reagents. It was also settled a timeline in order to promote courses offered by INCT-DT, as well as to support a greater interaction between members of INCT-DT as an increment. |
3. Message from the coordinator
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Alleviate the clinical manifestations and improve the life quality of those suffering with tropical diseases is the major goal of the National Institute of Science and Technology in Tropical Diseases (INCT-DT). The strategies used by the INCT-DT to achieve this goal involve: 1) a better understanding of the diseases pathogenesis, 2) improving the diagnosis, 3) identify biomarkers of disease progression, 4) identify new forms of treatment, 5) identify antigens that can be used as vaccines. Overcoming obstacles to achieving our goals requires an intensive collaboration between researchers of INCT-DT, as well as collaboration with other research groups inside and outside the country. The evaluation of our performance in this 1st year was highly positive in many aspects of our proposal. Research activities of high quality, post-docs, post-graduate students and graduate students have been benefited by the INCT- DT program; new technologies have been implemented and education and disclosure activities were conducted in endemic areas of schistosomiasis, leishmaniasis and leprosy. The strong collaboration between researchers of INCT-DT and the facilities we have for the studies involving patients with tropical diseases are the most important resources we have to achieve our goals and to get everyone involved with the INCT-DT program. |
4. Major Scientific-technical results
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The prevalence of chronic inflammatory and autoimmune diseases has increased in the last few years, comprising an important health problem. INCT-DT researchers have identified some antigens isolated from the tegument or egg of Schistosoma mansoni, such as Sm22.6. Sm29 and PIII which have the ability to modulate the allergic response in a murine model of asthma, and in vitro, these antigens are able to modulate the immune response of human cells from patients with asthma and chronic inflammatory disease such as HTLV-1. These antigens are future candidates for use in the management of chronic inflammatory and autoimmune diseases.
Other studies conducted in the multidisciplinary ambulatory of HTLV-1 at the Professor Edgard Santos Hospital, has shown that the morbidity associated with HTLV-1 reaches over 50% of the population infected. This morbidity is related to the fact that individuals infected with HTLV-1, that were previously considered as carriers of viral infection only, often present the clinical manifestations of neurogenic bladder or overactive bladder, erectile dysfunction, chronic periodontitis and sicca syndrome. These observations are of great relevance for clinical and public health since this viral infection is neglected due to the concept, now shown to be wrong by researchers of the Institute, that this virus only causes disease in a small number of patients (less than 5%). Data generated by the INCT-DT show that at least 50% of individuals infected with HTLV-1 actually develop some degree of neurological, periodontal or rheumatoid disease. The Community Participation Program for the control of helminthiasis and its impact on science and public health have demonstrated that research with the participation of the community, by combining the production of knowledge to a concrete practice, has enabled the community to understand the role of research and researcher for improvements in health. In the field of schistosomiasis there is the SchistoDB (www.SchistoDB.net) that is a resource for the scientific community who work with the disease. The genome sequencing of an organism of interest is a high point in research in this area. However, the raw data or text format (as normally found) is difficult to deal by the scientific community. The availability of a relational database that allows the searching of information and providing a web interface makes the genomic information useful for the community. The SchistoDB is a resource of great value in this sense. The SchistoDB had over 66 000 pages visited by researchers from around the world who use it to check the structure of a gene and search for new targets for control by drug or vaccine. In the subproject “Biomarkers associated with cardiac and cerebral Chagas disease” researches has identified several blood markers that help to predict the occurrence of two major complications of the disease: cardiac involvement and the occurrence of stroke. So far, we identified polymorphisms in the gene for IL-10 as a predictor of the occurrence of heart disease, and polymorphisms in COX2 gene as a predictor of the occurrence of stroke in patients with Chagas disease. The study of these genes and their functions has the potential not only to help predict these complications but also to identify disease mechanisms and support the development of treatment strategies directed at these mechanisms. |
5. Highlights
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One of the most important goals of the INCT-DT project is the training of human resources. Several graduate students (29 undergraduate students) and post-graduate (23 M.Sc. students and 23 PhD) and postdoctoral (4 students) has been participating in the project. Of these, a scientific initiation student and a master's degree student already completed their work.
Seven papers have been published by the group of INCT-DT researches and they have presents their work at some permitting meetings.
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Lists of publications
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1. Araujo M.I.; Campos R. A.; Cardoso L.S.; Oliveira S.C. and Carvalho E.M.
Immunomodulation of the Allergic Inflammatory Response: New Developments. Inflammation & Allergy - Drug Targets, 2010, 9, 73-82.
2. Cardoso, L. S.; Oliveira, S. C.; Góes, A. M.; Oliveira, R. R.; Pacífico, L. G.; Marinho, F. V.; Fonseca, C. T.; Cardoso, F. C.; Carvalho, E. M. and Araujo, M. I. Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation. Clinical and Experimental Immunology, doi:10.1111/j.1365-2249.2009.04084.
3. Oliveira, P.; Castro, N.M.; Muniz, A.L.; Tanajura, D.; Brandão, J.C.; Porto, A.F.; and Carvalho, E.M. Prevalence of Erectile Dysfunction in HTLV-1–Infected Patients and Its
Association with Overactive Bladder. UROLOGY 75 (5), 2010.
4. Costa, G.C.; Rocha, M.O.C.; Moreira, P.R.; Menezes, C.A.S.; Silva, M.R.; Gollob, K.J. and Dutra, W.O. Functional IL-10 Gene Polymorphism Is Associated with Chagas Disease Cardiomyopathy. The Journal of Infectious Diseases; 199:451– 4, 2009.
5. Bacellar, O.; Faria, D.; Nascimento, M.; Cardoso, T.M.; Gollob, K.J.; Dutra, W.O.; Scott, P. and Carvalho, E.M.Interleukin 17 Production among Patients with American Cutaneous Leishmaniasis. The Journal of Infectious Diseases; 200:75–8, 2009.
6. Dutra, W.O.; Menezes, C.A.S.; Villani, F.N.A.; Costa, G.C.; Silveira, A.B.M.; Reis, D. d’Ávila.; Gollob, K.J.Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease. Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 104(Suppl. I): 208-218, 2009.
7. Garlet, G.P.; Giozza, S.P.; Silveira,E.M.; Claudino, M.; Santos, S.B.; Avila-Campos, M.J.; Martins, Jr, W.; Cardoso, C.R.; Trombone, A.P.F.; Campanelli, A.P.; Carvalho, E.M.; and Silva, J.S. Association of Human T Lymphotropic Virus 1 Amplification of Periodontitis Severity with Altered Cytokine Expression in Response to a Standard
Periodontopathogen Infection. Clinical Infectious Diseases; 50:e11–8, 2010.
8. LOPES, D.O.; PAIVA, L.F.; AGUIAR, M.M.; CARDOSO, F.C.; RAJÃO, M.A.; PINHO, J.M.; CALIARI, M.V.; OLIVEIRA, R.C.; MELLO, S.M.; LEITE, L.C.C.; OLIVEIRA, S.C. Sm21.6 a novel EF-hand family protein member located on the surface of Schistosoma mansoni adult worm that failed to induce protection against challenge infection but reduced liver pathology. Vaccine, 27(2009) 4127-4135.
9. DURÃES, F.V.; CARVALHO, N.B.; MELO. T.T.; OLIVEIRA, S.C.; FONSECA, C.T.; IL-12 and TNF-alpha production by dendritic cells stimulated with Schistosoma mansoni schistosomula tegument is TLR4- and MyD88-dependent. Immunol. Lett, 2009;125(1): 72-77.
10.PINHO, J.M.R.; CARDOSO, F.C.; PINHEIRO, C.S.; CALIARI, M.V.; OLIVEIRA, F.M.S.; LEITE, L.C.C.; OLIVEIRA, S.C. Immunization with SmIg, a novel tegument protein from Schistosoma mansoni, fails to induce protection in mice but reduces livver pathology. Parasitology, 2009, 136, 1-10.
11. MARINHO, F.A.V.; PACÍFICO, L.G.G.; MIYOSHI, A.; AZEVEDO, V.; LE LEOIR, Y.; GUIMARÃES, V.D.; LANGELLA, P.; CASSALI, G.D.; FONSECA, C.T.; OLIVEIRA, S.C. An intranasal administration of Lactococcus lactis strains expressing recombinant interleukin-10 modulates acute allergic airway inflammation in a murine model. Clinical & Experimental Allergy, 2010, in press.
12. FAHEL, J.S.; MACEDO, G.C.; PINHEIRO, C.S.; CALIARI, M.V.; OLIVEIRA, S.C. IPSE/ALPHA-1 of Schistosoma mansoni egg induces enlargement of granuloma but does not alter Th2 balance after infection. Parasite Immunology, 2010, 32(5):345-53.
13. FARIAS, L.P.; CARDOSO, F.C.; MIYASATO, P.A.; MONTOYA, B.O.; TARARAM, C.A.; ROFFATO, H.K.; KAWANO, T.; GAZZINELLI, A.; OLIVEIRA, R.C.; COULSON, P.; WILSON, R.A.; OLIVEIRA, S.C.; LEITE, L.C.C. Schistosoma mansoni Stomatin like protein-2 is located in the tegument and induces partial protection against challenge infection. Plos Neglected Tropical Diseases, 4 (2): e597, 2010.
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Lists of works at Scientific Meetings
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1. Selection of novel recombinant antigens for serodiagnosis of human and canine visceral leishmaniasis, Brazil. Magalhaes F; Melo Neto OP; Pinheiro CGM; Nascimento MB; Teixeira MCA; Silvany M; Pereira AM; Santos LR; Conrado-dos-Santos, WL; Carvalho LCP; Oliveira GGS. XXXIV Congresso da Sociedade Brasileira de Imunologia, Setembro 2009, Salvador, BA.
2. Subcutaneous injection of montanide 720, used as an adjuvant, results in severe regional side-effects in dogs. Pinheiro CGM; Bahiense TC; Paixao LS; Carvalho, LCP; Oliveira GGS. XXXIV Congresso da Sociedade Brasileira de Imunologia, Setembro 2009, Salvador, BA.
3. Polimorfismo do gene da ciclooxigenase 2 (COX-2), mas não do gene da proteina ativador do araquidonato 5-lipoxigenase (ALOX5AP) está associado a acidente vascular cerebral e doença de Chagas em uma população com cardiomiopatia. Iuri S.Neville, Luciana M.B. Oliveira, Ana C.P. Ornellas, Carolina Cincurá, Daniela F. Menezes, Pedro A.P. Jesus, Davidson F. Pereira, Francisco J.F.B. Reis, Jamary Oliveira-Filho. VII Congresso Brasileiro de Doenças Cerebrovasculares, outubro de 2009, Vila Velha, Espírito Santo.
4. A resposta imune protetora induzida pelo tegumento de esquistossômulos do schistosoma mansoni mais adjuvante de freund induz dano no tegumento de verme adulto. Tatiane T.M, Fernanda V.D., Paulo M.Z.C, Cristina T.F. XXI Congresso de Parasitologia. II Encontro de Parasitologia do MERCOSUL. Novos Horizontes em Parasitologia, outubro de 2009, Foz do Iguaçu, Paraná.
5. Production of In vitro Gamma-IFN In Response to Corynebacterium pseudotuberculosis Antigens: Pilot For In Vitro Immunodiagnostic Kit Of Human Tuberculosis. Guedes,R.G.D.; Costa, L.F; Andrade,J.A.F.; Macêdo,L.S; Carneiro, V.L; Souza, J.S.M; Silva, FRS; Moreira, C.A; Rocha, D.J.P.G.; Meyer,R. E; Freire, SM. 39a Reunião Anual da SBBq, 2010, Foz do Iguaçu, Paraná.
6. Multivariate analysis as tool for studying the influence of multiple polymorphisms as markers of susceptibility to chagasic cardiomyopathy. Costa, Germano Carneiro; Melo, Diego Felipe Silva Abreu; Rocha, Manoel Otávio da Costa; Gollob, Kenneth John; Dutra, Walderez Ornelas. XXXIV Congresso da Sociedade Brasileira de Imunologia, Setembro 2009, Salvador, BA.
7. Multivariate analysis as tool for studying the influence of multiple polymorphisms as markers of susceptibility to chagasic cardiomyopathy. Costa, Germano Carneiro; Melo, Diego Felipe Silva Abreu; Rocha, Manoel Otávio da Costa; Gollob, Kenneth John; Dutra, Walderez Ornelas. International Symposium on the Centenary of Chagas disease Discovery, 2009.
8. O papel das células T regulatórias e IL-10 na modulação da Asma Alérgica induzida
por antígenos do Schistosoma mansoni e as perspectivas de Imunoterapia, Sergio Costa Oliveira, Lucila Grossi Pacifico, Luciana Cardoso, Maria Ilma Araujo, Edgar Carvalho, apresenatdo no II Ciclo de Palestras em Imunologia: Um olhar sobre a Imunoterapia em 21/08/2009 em Porto Alegre-RS.
9.Tegument proteins and innate immunity receptors at the interface of Schistosoma mansoni, Sergio Costa Oliveira,Fernanda do Valle Duraes, Cristina Toscano Fonseca, Carina Pinheiro, apresentado no Workshop - Schistosoma mansoni Post-Genomics at the Host-Parasite Interface em 08/03/2010, no Instituto Butantan - São Paulo/SP.
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Abstracts of the published papers
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Inflammation & Allergy - Drug Targets, 2010, 9, 73-82 1871-5281/10 $55.00+.00 © 2010 Bentham Science Publishers Ltd.
Immunomodulation of the Allergic Inflammatory Response: New Developments
M.I. Araujo*, R. A. Campos, L.S. Cardoso, S.C. Oliveira and E.M. Carvalho
Serviço de Imunologia, Hospital Universitário Prof. Edgard Santos, Universidade Federal da Bahia, Salvador, BA,Brazil
Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil; The National Institute of Science and Technology in Tropical Diseases (INCT-DT-CNPq); Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
Abstract: Studies of the molecular mechanisms associated with allergic diseases have lead to a better understanding of the complex processes that underlie their pathogenesis. These mechanisms involve Th2- and Th1-type cells and also some recently described cytokines, such as IL-25 and IL-33. Regulatory mechanisms of allergic inflammation have also been identified. For instance, IL-10, a cytokine produced by many cell types, promotes a decrease in IgE production, and inhibits the release of histamine and other inflammatory mediators by mast cells. Recently, a variety of regulatory cells have been discovered, which, either by direct contact or through the production of IL-10 and/or TGF-β, can inhibit the allergic inflammatory response. IL-10 is produced in high levels by cells of helminth-infected individuals. There is some evidence that such infections protect against the development of allergic diseases. In asthmatic individuals living in endemic areas of schistosomiasis, it has been shown in in vitro studies that there is a modulation of the Th2 response, both by mechanisms involving IL-10, which is produced mainly by monocytes and CD4+CD25+ T regulatory cells, and also by the expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) in CD4+ T cells. Studies using parasite antigens to induce the modulation of allergic inflammatory response are being conducted by several groups of researchers and represent new perspectives for the treatment of allergic diseases.
Keywords: Asthma, Allergy, Immunoregulation, atopy.
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Clinical and Experimental Immunology ORIGINAL ARTICLE
doi:10.1111/j.1365-2249.2009.04084.x
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Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation
L. S. Cardoso,* S. C. Oliveira,†, A. M. Góes,† R. R. Oliveira,*L. G. Pacífico,† F. V. Marinho,†C. T. Fonseca,† F. C. Cardoso,† E. M. Carvalho*‡§ and M. I. Araujo*‡§
*Serviço de Imunologia, Hospital UniversitárioProf Edgard Santos, Universidade Federal da Bahia, Salvador, BA, †Departamento de Imunologia e Bioquímica, ICB, Universidade Federal Universidade de Minas Gerais, Belo Horizonte, MG, ‡Escola Bahiana de Medicina e Saúde Pública, Salvador, BA, Brazil, e Instituto Nacional de Ciência e Tecnologia de Doenças Tropicais (INCT-DT), Salvador, BA,Brazil
Summary
Schistosoma mansoni infection has been associated with protection against allergies. The mechanisms underlying this association may involve regulatory cells and cytokines. We evaluated the immune response induced by the S.mansoni antigens Sm22·6, PIII and Sm29 in a murine model of ovalbumin (OVA)-induced airway inflammation. BALB/c mice were sensitized with subcutaneously injected OVA-alum and challenged with aerolized OVA. Mice were given three doses of the different S. mansoni antigens. Lung histopathology, cellularity of bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in lung were evaluated. Immunoglobulin (Ig)E levels in serum and cytokines in BAL were also measured. Additionally, we evaluated the frequency of CD4+forkhead box P3 (FoxP3)+ T cells in cultures stimulated with OVA and the expression of interleukin (IL)-10 by these cells. The number of total cells and eosinophils in BAL and the levels of OVA-specific IgE were reduced in the immunized mice. Also, the levels of IL-4 and IL-5 in the BAL of mice immunized with PIII and Sm22·6 were decreased, while the levels of IL-10 were higher in mice immunized with Sm22·6 compared to the nonimmunized mice. The frequency of CD4+FoxP3+ T cells was higher in the groups of mice who received Sm22·6, Sm29 and PIII, being the expression of IL-10 by these cells only higher in mice immunized with Sm22·6. We concluded that the S. mansoni antigens used in this study are able to downmodulate allergic inflammatory mediators in a murine model of airway inflammation and that the CD4+FoxP3+ T cells, even in the absence of IL-10 expression, might play an important role in this process.
Keywords: allergy, asthma, vaccines
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UROLOGY 75: 1100–1103, 2010. © 2010 Elsevier Inc.
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Prevalence of Erectile Dysfunction in HTLV-1–Infected Patients and Its Association with Overactive Bladder
Paulo Oliveira, Néviton M. Castro, André L. Muniz, Davi Tanajura, Julio C. Brandão, Aurélia F. Porto, and Edgar M. Carvalho
OBJECTIVES
To determine the prevalence of erectile dysfunction (ED) in human T-cell lymphotropic virus type I (HTLV-I)-infected patients, and its association with overactive bladder (OB). METHODS In a cross-sectional study, 111 male patients with positive serology for HTLV-I (by enzymelinked immunosorbent assay and Western blot) were examined between October 2003 and December 2006. Exclusion criteria were age _18 and _80 years, other neurological diseases, penile prosthesis, neoplasm, and psychological and mental disease. Patients were evaluated by a urologist and neurologist. ED was determined by application of the abridged form of 5-item International Index of Erectile Function (IIEF-5). ED was defined as IIEF-5 _ 21. OB was determined by International Continence Society criteria. Using the Expanded Disability Status Scale (EDSS) to determine disautonomy status, a neurologist classified all patients as either asymptomatic carriers (EDSS _ 0), “oligosymptomatic myelopathy” (EDSS _ 0 e _ 2), or HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP); (EDSS _ 2). Diagnosis of HAM/TSP was performed according to World Health Organization recommendations.
RESULTS
Of the total of 111 patients, 6 were excluded and 105 were analyzed. The mean age was 48 _ 10.7 years. ED was observed in 55.2%. ED was documented in all patients who had HAM/TSP, in 79% of the group with EDSS _ 0 and _2, and in 35.9% of HTLV-1–infected individuals with EDSS _ 0. OB was detected in 93.75%, 33.3%, and 4.6%, respectively. Moreover, there was an association observed between ED and OB.
CONCLUSIONS
ED is a frequent disease in HTLV-I-infected individuals, and the prevalence is directly correlated to the degree of neurological disability measured by EDSS. ED was strongly associated with OB symptoms.
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The Journal of Infectious Diseases 2009; 199:451– 4
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Functional IL-10 Gene Polymorphism Is Associated with Chagas Disease Cardiomyopathy
Germano C. Costa, Manoel Otávio da Costa Rocha, Paula Rocha Moreira, Cristiane Alves Silva Menezes, Micena R. Silva, Kenneth J. Gollob, and Walderez O. Dutra
Laboratory of Cell-Cell Interactions, Department of Morphology; Laboratory of Lymphocyte Biology, Department of Biochemistry and Immunology; and Program of Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
This study was designed to determine whether the functional IL-10 gene polymorphism _1082G/A is associated with the development of cardiomyopathy in individuals infected with Trypanosoma cruzi and whether interleukin (IL)–10 expression can be correlated with patients’ cardiac function. Our results demonstrated that the polymorphic allele, which correlates with lower expression of IL-10, was associated with the development of Chagas disease cardiomyopathy. Accordingly, correlative analysis showed that low IL-10 expression was associated with worse cardiac function, as determined by leftventricular ejection fraction values. Therefore, the IL-10 gene polymorphism and IL-10 expression are important in determining susceptibility to chagasic cardiomyopathy.
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The Journal of Infectious Diseases 2009; 200:75–8
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Interleukin 17 Production among Patients with American Cutaneous Leishmaniasis
Olívia Bacellar, Daniela Faria, Márcia Nascimento, Thiago M. Cardoso, Kenneth J. Gollob, Walderez O. Dutra, Phillip Scott, and Edgar M. Carvalho
Servico de Imunologia, Hospital Universitário Prof. Edgard Santos, Universidade Federal da Bahia, Salvador-Bahia; Departamento de Morfologia; Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; and Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia
Interleukin 17 (IL-17) plays a critical role in inflammation and autoimmunity. Very little is known about IL-17 in protozoa infection. Here, we show that lymphocytes obtained from patients with mucosal leishmaniasis and cutaneous leishmaniasis produce higher levels of IL-17 than do lymphocytes obtained from uninfected control subjects (P ! .01). There was a tendency for tissue obtained from patients with mucosal leishmaniasis to contain a higher number of cells expressing IL-17, compared with tissue obtained from patients with cutaneous leishmaniasis, and there was a direct correlation between the number of cells expressing IL-17 and the presence of cellular inflammation at the lesion site (r 2p0.86; P ! .001). These data support the role of IL-17 in the pathogenesis of the inflammatory reaction in leishmaniasis.
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Mem Inst Oswaldo Cruz, Rio de Janeiro, Vol. 104(Suppl. I): 208-218, 2009
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Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease
Walderez Ornelas Dutra, Cristiane Alves Silva Menezes, Fernanda Nobre Amaral Villani, Germano Carneiro da Costa, Alexandre Barcelos Morais da Silveira, Débora d’Ávila Reis, Kenneth J Gollob
Departamento de Morfologia Departamento de Bioquímica-Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Av. Presidente Antônio Carlos 6627, 31.270-901 Belo Horizonte, MG, Brasil; Robarts Research Institute, University of Western Ontario, London, Canadá; Departamento de Morfologia, Instituto de Ciências Biomédicas, Universidade Federal de Uberlândia, Uberlândia, MG, Brasil
Perhaps one of the most intriguing aspects of human Chagas disease is the complex network of events that underlie the generation of protective versus pathogenic immune responses during the chronic phase of the disease. While most individuals do not develop patent disease, a large percentage may develop severe forms that eventually lead to death. Although many efforts have been devoted to deciphering these mechanisms, there is still much to be learned before we can fully understand the pathogenesis of Chagas disease. It is clear that the host’s immune response is decisive in this process. While characteristics of the parasite influence the immune response, it is becoming evident that the host genetic background plays a fundamental role in the establishment of pathogenic versus protective responses. The involvement of three complex organisms, host, parasite and vector, is certainly one of the key aspects that calls for multidisciplinary approaches towards the understanding of Chagas disease. We believe that now, one hundred years after the discovery of Chagas disease, it is imperative to continue with highly interactive research in order to elucidate the immune response associated with disease evolution, which will be essential in designing prophylactic or therapeutic interventions.
Key words: pathology - protection - T-cells - immunoregulation - Chagas disease
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Clinical Infectious Diseases 2010; 50:e11–8
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Association of Human T Lymphotropic Virus 1Amplification of Periodontitis Severity with Altered Cytokine Expression in Response to a Standard Periodontopathogen Infection
Gustavo Pompermaier Garlet, Silvana Pereira Giozza, Elcia Maria Silveira,1 Marcela Claudino, Silvane Braga Santos, Mario Julio Avila-Campos, Walter Martins, Jr, Cristina Ribeiro Cardoso, Ana Paula Favaro Trombone, Ana Paula Campanelli, Edgar Marcelino Carvalho, and João Santana Silva
Department of Biological Sciences, School of Dentistry of Bauru, and Department of Microbiology, Institute of Biomedical Sciences, São Paulo University, São Paulo, Serviço de Imunologia, Hospital Universitário Professor Edgar Santos, Universidade Federal da Bahia, Salvador, Department of Periodontics, Dentistry School of University of Ribeirão Preto, and Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, São Paulo University, Ribeirão Preto, and Department of Biological Sciences, Federal University of Triângulo Mineiro, Triângulo Mineiro, Brazil
Background.
Periodontal diseases (PDs) are infectious diseases in which periodontopathogens trigger chronic inflammatory and immune responses that lead to tissue destruction. Recently, viruses have been implicated in the pathogenesis of PDs. Individuals infected with human T lymphotropic virus 1 (HTLV-1) present with abnormal oral health and a marked increased prevalence of periodontal disease.
Methods.
In this study, we investigated the patterns of periodontopathogen infection and local inflammatory immune markers in HTLV-1–seropositive individuals with chronic periodontitis (CP/HTLV-1 group) compared with HTLV-1–seronegative individuals with chronic periodontitis (CP group) and periodontally healthy, HTLV-1–seronegative individuals (control group). Results. Patients in the CP/HTLV-1 group had significantly higher values of bleeding on probing, mean probing depth, and attachment loss than patients in the CP group. The expression of tumor necrosis factor a and interleukin (IL) 4 was found to be similar in the CP and CP/HTLV-1 groups, whereas IL-12 and IL-17 levels trended toward a higher expression in the CP/HTLV-1 group. A significant increase was seen in the levels of IL-1b and interferon g in the CP/HTLV-1 group compared with the CP group, whereas expression of the regulatory T cell marker FOXp3 and IL-10 was significantly decreased in the lesions from the CP/HTLV-1 group. Interestingly, similar frequency and/or load of periodontopathogens (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola,and Aggregatibacter actinomycetemcomitans) and frequency of viruses (herpes simplex virus 1, human cytomegalovirus, and Epstein-Barr virus) characteristically associated with PDs were found in the CP/HTLV and CP groups. Conclusions. HTLV-1 may play a critical role in the pathogenesis of periodontal disease through the deregulation of the local cytokine network, resulting in an exacerbated response against a standard periodontopathogen infection. |
Parasite Immunol. 2010 May;32(5):345-53.
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IPSE/alpha-1 of Schistosoma mansoni egg induces enlargement of granuloma but does not alter Th2 balance after infection.
Fahel JS, Macedo GC, Pinheiro CS, Caliari MV, Oliveira SC.
Department of Biochemistry and Immunology, Federal University of Minas Gerais,
Belo Horizonte, Minas Gerais 31270-901, Brazil.
Schistosomiasis is a parasitic disease with more than 200 million people infected worldwide. The formation of granulomas around eggs trapped in the liver is the main cause of disease morbidity. Therefore, the aim of this investigation was to characterize the immunopathological response induced by the recombinant (r) IPSE/alpha-1 egg protein in mice. Herein, we have shown that splenocytes from mice immunized with rIPSE/alpha-1 produced IFN-gamma, TNF-alpha, IL-4, IL-5 and IL-13 characterizing a mixed Th1/Th2 type of immune response. Pathological analysis of the liver revealed that there was no alteration in the number of eggs and granulomas; however, we observed an increase in granuloma area in immunized mice. Furthermore, eosinophil peroxidase assay showed that there was no alteration in the eosinophil infiltration in the liver; however, n-acetyl-beta-glucosaminidase measurement revealed an increase in macrophage activity. Despite the alteration in the profile of liver inflammatory cells in rIPSE immunized mice, the production of chemokines such as CCL2, CCL3, CCL5 and CCL11 was unaltered compared with the control group. In conclusion, IPSE/alpha-1 immunization induces a mixed Th1/Th2 type of immune response and enlargement of hepatic granuloma caused by an increased macrophage activity, but does not alter Th2 cytokines following infection.
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An intranasal administration of Lactococcus lactis strains expressing recombinant interleukin-10 modulates acute allergic airway inflammation in a murine model.
Marinho FA, Pacífico LG, Miyoshi A, Azevedo V, Le Loir Y, Guimarães VD, Langella P, Cassali GD, Fonseca CT, Oliveira SC.
Department of Biochemistry and Immunology, Biological Sciences Institute, Federal
University of Minas Gerais Minas Gerais, Belo Horizonte, MG, Brazil.
Summary Background Around 300 million people world-wide suffer from asthma, and the prevalence of allergic diseases has increased. Much effort has been used in the study of mechanisms involved in the immune response observed in asthma to intervene for the treatment of this condition. During inflammation in asthma, Th2 cytokines and eosinophils are essential components of the host immune system. Furthermore, for therapeutic interventions against this disease, IL-10 is an important cytokine because it has a central role in the regulation of inflammatory cascades. Objective To evaluate the immunomodulatory effect of Lactococcus lactis strains expressing recombinant IL-10 in a mouse model of ovalbumin (OVA)-induced acute airway inflammation. Methods L. lactis expressing recombinant IL-10 in a cytoplasmic (LL-CYT) or secreted form (LL-SEC) and wild-type (LL-WT) were used. IL-10 production by the recombinant strains was evaluated by ELISA. After an intranasal administration of L. lactis producing recombinant IL-10 and the induction of acute allergic airway inflammation in mice, blood samples were collected to detect IgE anti-OVA, and bronchoalveolar lavage (BAL) was harvested for eosinophil count. Additionally, the lungs were collected for the detection of the eosinophil peroxidase (EPO) activity, measurement of cytokines and chemokines and evaluation of pathology. Results Mice that received LL-CYT and LL-SEC strains showed a significant decrease in eosinophils numbers, EPO activity, anti-OVA IgE and IgG1 levels, IL-4 and CCL3 production and pulmonary inflammation and mucus hypersecretion, compared with the asthmatic group. Only the LL-CYT/OVA group showed reduced levels of IL-5, CCL2, CCL5 and CCL11. Conclusion Treatment with L. lactis producing recombinant IL-10 used in this study (LL-CYT and LL-SEC) modulated experimental airway inflammation in the mouse model independently of Treg cells. Additionally, the LL-CYT strain was more efficient in the suppression of lung inflammation.
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Parasitology. 2010 Jun;137(7):1079-88. Epub 2009 Oct 16.
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Immunization with SmIg, a novel tegument protein from Schistosoma mansoni, fails to induce protection in mice but reduces liver pathology.
Pinho JM, Cardoso FC, Lopes DO, Pinheiro CS, Caliari MV, Oliveira FM, Leite LC, Oliveira SC.
Department of Biochemistry and Immunology, Biological Sciences Institute, Federal University of Minas Gerais Minas Gerais, Belo Horizonte, MG, Brazil.
Proteins associated with the schistosome tegument are of great importance for the development of new intervention strategies since they may be exposed on the surface of the parasite. Herein, we have isolated a cDNA clone encoding for the Schistosoma mansoni SmIg and its recombinant protein was tested as a potential vaccine candidate. Initially, its amino acid sequence was analysed by bioinformatics and shown to possess an N-terminal signal peptide, a C-terminal transmembrane helix, 4 glycosylation sites, an immunoglobulin conserved domain and 73% similarity with a hypothetical S. japonicum protein of unknown function. SmIg was produced by E. coli as a recombinant protein (rSmIg) and its protective effectiveness was evaluated against S. mansoni infection with 100 cercariae in a murine model. Mice immunized with rSmIg induced an immune response characterized by dominant IgG1 isotype and significant levels of IFN-gamma, TNF-alpha, IL-10 and IL-4. Although immunogenic, the recombinant vaccine failed to induce worm burden reduction when compared to the infected control group. However, rSmIg-immunized mice had significant reductions of liver granuloma volume and fibrosis content by 31.8% and 49%, respectively. In conclusion, SmIg is a new tegument protein from S. mansoni that plays an important role in reducing pathology induced by parasite infection.
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Schistosoma mansoni Stomatin like protein-2 is located in the tegument and induces partial protection against challenge infection.
Farias LP, Cardoso FC, Miyasato PA, Montoya BO, Tararam CA, Roffato HK, Kawano T, Gazzinelli A, Correa-Oliveira R, Coulson PS, Wilson RA, Oliveira SC, Leite LC.
Centro de Biotecnologia, Instituto Butantan, São Paulo, SP, Brazil.
BACKGROUND:
Schistosomiasis affects more than 200 million individuals worldwide, with a further 650 million living at risk of infection, constituting a severe health problem in developing countries. Even though an effective treatment exists, it does not prevent re-infection, and the development of an effective vaccine still remains the most desirable means of control for this disease.
METHODOLOGY/PRINCIPAL FINDINGS:
Herein, we report the cloning and characterization of a S. mansoni Stomatin-like protein 2 (SmStoLP-2). In silico analysis predicts three putative sites for palmitoylation (Cys11, Cys61 and Cys330), which could contribute to protein membrane association; and a putative mitochondrial targeting sequence, similar to that described for human Stomatin-like protein 2 (HuSLP-2). The protein was detected by Western blot with comparable levels in all stages across the parasite life cycle. Fractionation by differential centrifugation of schistosome tegument suggested that SmStoLP-2 displays a dual targeting to the tegument membranes and mitochondria; additionally, immunolocalization experiments confirm its localization in the tegument of the adult worms and, more importantly, in 7-day-old schistosomula. Analysis of the antibody isotype profile to rSmStoLP-2 in the sera of patients living in endemic areas for schistosomiasis revealed that IgG1, IgG2, IgG3 and IgA antibodies were predominant in sera of individuals resistant to reinfection as compared to those susceptible. Next, immunization of mice with rSmStoLP-2 engendered a 30%-32% reduction in adult worm burden. Protective immunity in mice was associated with specific anti-rSmStoLP-2 IgG1 and IgG2a antibodies and elevated production of IFN-gamma and TNF-alpha, while no IL-4 production was detected, suggesting a Th1-predominant immune response. CONCLUSIONS/SIGNIFICANCE:
Data presented here demonstrate that SmStoLP-2 is a novel tegument protein located in the host-parasite interface. It is recognized by different subclasses of antibodies in patients resistant and susceptible to reinfection and, based on the data from murine studies, shows protective potential against schistosomiasis. These results indicate that SmStoLP-2 could be useful in a combination vaccine.
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IL-12 and TNF-alpha production by dendritic cells stimulated with Schistosoma mansoni schistosomula tegument is TLR4- and MyD88-dependent.
Durães FV, Carvalho NB, Melo TT, Oliveira SC, Fonseca CT.
Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, A. Belo Horizonte, Minas Gerais, Brazil.
Schistosoma mansoni schistosomula are the most susceptible parasite life stage to host immune system attack. Complex host-parasite interactions take place on Schistosoma tegument, which is a unique double membrane structure involved in nutrition and immune evasion. Herein, we have demonstrated that schistosomula tegument (Smteg) activates Dendritic cells to produce IL-12p40, TNF-alpha and also to up-regulate the co-stimulatory molecules CD40 and CD86. Moreover, using DCs derived from MyD88-, TLR2-, TLR4- and TLR9-deficient mice we have shown that the ability of Smteg to activate DCs to produce IL-12 and TNF-alpha involves TLR4/Smteg interaction and MyD88 signaling pathway. Finally, our findings lead us to conclude that TLR4 is a key receptor involved in Smteg induction of pro-inflammatory cytokines.
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Sm21.6 a novel EF-hand family protein member located on the surface of Schistosoma mansoni adult worm that failed to induce protection against challenge infection but reduced liver pathology.
Lopes DO, Paiva LF, Martins MA, Cardoso FC, Rajão MA, Pinho JM, Caliari MV, Correa-Oliveira R, Mello SM, Leite LC, Oliveira SC.
Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Avenida Antonio Carlos 6627, Pampulha, Belo Horizonte 31270-901, MG, Brazil.
Schistosomiasis continues to be a significant public health problem that affects 200 million people worldwide. This is one of the most important parasitic diseases, and one whose effective control is unlikely in the absence of a vaccine. In this study, we have isolated a cDNA clone encoding the Schistosoma mansoni Sm21.6 protein that has 45% and 44% identity with Sm22.6 and Sj21.7 EF-hand containing antigens, respectively. Confocal microscopy analysis revealed that Sm21.6 is a membrane-associated protein localized on the S. mansoni adult worm. Mouse immunization with rSm21.6 induced a mixed Th1/Th2 cytokine profile and no protection against infection. However, vaccination with rSm21.6 reduced by 28% of liver granuloma numbers, 21% of granuloma area and 34% of fibrosis. Finally, rSm21.6 was recognized by sera from individuals resistant to reinfection compared with patients susceptible to reinfection and this molecule should be further studied as potential biomarker for disease resistance. In conclusion, Sm21.6 is a new tegument protein from S. mansoni that plays an important role in reducing pathology induced by parasite infection.
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External Evaluation
Click here to see the external evaluation, March 2010
