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Desenvolvimento de vacinas recombinantes contra malária humana e teste in vivo em modelo murino

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LEONEIDE ÉRICA MADURO BOUILLET DESENVOLVIMENTO DE VACINAS RECOMBINANTES CONTRA MALÁRIA HUMANA E TESTE IN VIVO EM MODELO MURINO ORIENTADOR: Prof. OSCAR BRUNA ROMERO BELO HORIZONTE MAIO 2009 i LEONEIDE ÉRICA MADURO BOUILLET DESENVOLVIMENTO DE VACINAS RECOMBINANTES CONTRA MALÁRIA HUMANA E TESTE IN VIVO EM MODELO MURINO Tese de Doutorado apresentada ao curso de Pós-graduação do Departamento de Microbiologia do Instituto de Ciências Biológicas da UFMG como requisito parcial para obtenção do grau de doutora em Microbiologia. ORIENTADOR: Prof. OSCAR BRUNA ROMERO BELO HORIZONTE MAIO 2009 i ii Trabalho realizado no Laboratório de Agentes Recombinantes do Departamento de Microbiologia do Instituto de Ciências Biológicas da Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, com auxílio financeiro: Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) - Bolsa de Doutorado/ 2005 – 2009. Fundação Oswaldo Cruz: projeto PDTIS - Vacinas para malária CNPq Projeto aprovado pelo Comitê de Ética em Experimentação Animal (CETEA) da UFMG, protocolo nº 140/2005. Foram feitos depósitos de patentes com os resultados deste projeto: INPI (Instituto Nacional de Propriedade Industrial) A) Número pedido: PI0706003-3 A2 Data depósito: 26/10/2007 Título: Sequência geneticamente modificada do antígeno AMA-1 de Plasmodium vivax, proteína recombinante AMA-1 e adenovírus geneticamente modificado que expressa o antígeno AMA-1 recombinante. Inventores: BOUILLET, L. E. M., SOARES, I., GAZZINELLI, R. T., BRUNAROMERO, O. Publicado em: Revista da Propriedade Industrial - RPI no 2007 (23/06/2009), com retificação em RPI no 2060 (29/06/2010) B) Número pedido: PI0705990-6 A2 Data depósito: 26/10/2007 Título:Sequência geneticamente modificada do antígeno MSP-1, proteína recombinante MSP-1 e adenovírus geneticamente modificado que expressa o antígeno MSP-1. Inventores: BOUILLET,L.E.M.,RODRIGUES,M.M., GAZZINELLI, R.T., BRUNAROMERO, O. Publicado em: Revista da Propriedade Industrial - RPI no 2007 (23/06/2009) World Intellectual Property Organization /Patent Cooperation Treaty – PCT Número pedido: PCT/ BR 2009/000130 Data depósito: 05/05/2009 Título: Genetically-modified sequences encoding Plasmodium vivax antigens, vaccine composition containing recombinant purified antigens and recombinant viruses that express those antigens and prime-boost vaccination protocol against Malaria. Inventores: BOUILLET, L. E. M., CASTELUBER, M. C. F., de ANDRADE, B P, BRITO, C. F. A., CARRARA, C.L, FONSECA, F. G., SOARES, I. S., M.M.RODRIGUES,, GAZZINELLI, R. T., BRUNA-ROMERO, O. Publicado em: WIPO Número WO/2010/127420 (11/11/2010) iii A minha mãe, Zuleide, obrigada pela educação e pelos valores – peças fundamentais na construção do meu cárater – e por sempre acreditar no meu potencial. Com todo amor e gratidão. iv “Deus nos fez perfeitos e não escolhe os capacitados, capacita os escolhidos. Fazer ou não fazer algo, só depende de nossa vontade e perseverança”. Albert Eistein. v AGRADECIMENTOS Agradeço a minha família pelo carinho, incentivo e apoio constante, em especial a minha Mãe. Agradeço ao Fabinho pelo apoio e companheirismo. Ao meu orientador Oscar pela oportunidade de aprendizado, pelo apoio e valiosos ensinamentos que, além de me engrandecerem profissionalmente, me fizeram crescer como pessoa. Agradeço as minhas estagiárias, Natália e Mariana, que na realidade são mais que estagiárias, são dois anjinhos na minha vida. Obrigada pela dedicação no estágio e principalmente pelo trabalho árduo. A ajuda de vocês foi imprescindível para o desenvolvimento desta tese. Às minhas amigas meus sinceros agradecimentos pelos inestimáveis conselhos e risos constantes. Às amigas do LAR, Bruninha, Cristina, Camila e Maria Rosa. Com a presença de vocês o nosso LAR ficava mais agradável. Ao laboratório de Imunoparasitologia – Departamento de Bioquímica – ICB/UFMG pela utilização de suas instalações e pelo apoio durante o início deste projeto. Ao João Rodrigues pelas dicas preciosas e pelo incansável apoio. À Tânia Mara, que com seu jeito amigo e prestativo, sempre me ajudou nas horas difíceis. À FIOCRUZ, FAPEMIG e CNPq pelo apoio financeiro. vi RESUMO Vacinas que promovem a proteção contra a malária são urgentemente necessárias para o controle da doença. O antígeno 1 de membrana apical (AMA-1) e o fragmento de 19kDa da proteína 1 de superfície de merozoíto (MSP-119) são os principais candidatos a vacina contra o estágio sanguíneo da malária devido a estudos de proteção encorajadores em animais e humanos. Neste estudo, nós investigamos o efeito de candidatos a vacinas contra P.vivax geneticamente modificados, PvAMA-1 e PvMSP-119, em diferentes combinações de protocolos de imunizações do tipo dose-reforço. Com este objetivo foram construídos adenovírus recombinantes expressando PvAMA-1 e PvMSP-119 para modular e ativar uma resposta celular efetiva. Além disso, os polipeptídeos equivalentes foram expressos em E.coli, purificados e utilizados para induzir resposta humoral. Após a caracterização dos antígenos vacinais, os vírus recombinantes e as proteínas formuladas com o adjuvante Montanide ISA 720 foram empregados na imunização de camundongos BALB/c. A vacinação com os protocolos de imunização Ad/Ad, Ad/prot, prot/prot e prot/Ad levou à produção de IgG anti- PvAMA-1 e anti-PvMSP-119 específica em todos os grupos vacinais. No entanto, os protocolos prot/prot e prot/Ad foram mais eficientes, produzindo elevados títulos de anticorpos, tanto para PvAMA-1 como para PvMSP-119. PvAMA-1 foi capaz de induzir a proliferação celularantígeno específica, sendo que os protocolos Ad/Ad e prot/prot foram capazes de induzir maiores níveis de proliferação celular que os protocolos prot/Ad e Ad/prot. PvMSP-119 foi capaz de ativar resposta imune celular do tipo Th1, com elevados níveis de produção de IFN-γ, IL-2 e TNF-α. Além disso, foi capaz de induzir a produção de IL-10, mas não desencadeou a produção de IL-4. Desta forma, pode-se concluir que a vacinação com os protocolos de imunização do tipo dose-reforço prot/prot, prot/Ad foram melhores em induzir resposta humoral e celular, já o protocolo Ad/Ad induziu uma melhor resposta celular. Estes resultados são encorajadores para estudos pré-clínicos em macacos Aotus spp e sugere-se a utilização dos protocolos prot/prot, prot/Ad e Ad/Ad. Palavras-chaves: Adenovírus humano sorotipo 5, vacinas recombinantes, malária, AMA-1, MSP-119 vii ABSTRACT Vaccines that provide protection against malaria are urgently needed for disease control. Several studies have demonstrated that Apical membrane antigen-1 (AMA-1) and 19KDa fragment of merozoit surface protein (MSP-119) are the main vaccine candidates against blood stages of malaria due to their capacity to induce protection in humans and animals. In this study, we investigated the effect of P. vivax vaccine candidates genetically modified PvAMA-1 and PvMSP-1 in different combinations of prime-boost immunization protocols. With this aim we constructed recombinant adenoviruses expressing PvAMA-1 and PvMSP-1 to active and modulate an effective type of T-cell response. Equivalent recombinant polypeptides purified from E.coli-expressing bacteria were used to induce humoral response. After the characterization of vaccine antigens, BALB/c mice were immunized with virus and proteins formulated in Montanide ISA 720 adjuvant. The animals vaccinated with the following immunization protocols Ad/Ad, Ad/prot, prot/prot and prot/Ad generated specific anti-PvAMA-1 and anti-PvMSP-119 IgG antibodies. However, the prime-boost protocols prot/prot and prot/Ad efficiently enhanced antibodies response, showing high antibody titers to AMA-1 and MSP-119. PvAMA-1 was able to induce specific antigen-cellular proliferation and the protocols Ad/Ad and prot/prot were able to induce highest levels of cell proliferation. PvMSP-119 was able of elicited cell responses predominantly a Th1-biased, inducing higher levels of IFN-γ, IL-2 e TNF-α. Furthermore, it was able to induce the production of IL-10 but not triggered the production of IL-4. In such way, we conclude that immunization with the prime-boost protocols prot/prot and prot/Ad induced efficient humoral and cellular immune response. In the other hand, Ad/Ad elicited efficient cellular immune response. 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PLoS Pathog 2012, 8:e1003099. doi:10.1186/1475-2875-12-388 Cite this article as: Miranda et al.: Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria. Malaria Journal 2013 12:388. Submit your next manuscript to BioMed Central and take full advantage of: Convenient online submission Thorough peer review No space constraints or color figure charges Immediate publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit 6.3 – Artigo científico 3 84 Artigo em preparação para submissão. Title: A neuroprotective effect of glutamate receptors antagonist MK801 in experimental cerebral malaria long-term cognitive and behavioral outcomes. Miranda'et'al.,'2015'(In'preparation)' A neuroprotective effect of glutamate receptor antagonist MK801 in experimental cerebral malaria long-term cognitive and behavioral outcomes Aline Silva de Mirandaa,b,c, Fátima Branta,b, Luciene Bruno Vieirad, Natália Pessoa Rochac,d, Érica Leandro Marciano Vieirac, Gustavo Henrique Souza Rezendee, Pollyana Maria de Oliveira Pimentelb, Marcio F.D. Moraese, Marcus Vinicius Gomezf, Fabíola Mara Ribeirob, Richard M Ransohoffg, Fabiana Simão Machadoa,b,' Milene Alvarenga Rachidh, Antônio Lúcio Teixeiraa,b,c aPostgraduate Program in Health Sciences: Infectious Diseases and Tropical Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. bDepartment of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. cInterdisciplinary Laboratory of Medical Investigation, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. dDepartment of Pharmacology,' Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.' eDepartment of Physiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. fNational Institute of Science and Technology in Molecular Medicine, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. gNeuroinflammation Research Center, Mellen Center for MS Treatment and Research; and Cleveland Clinic Lerner College of Medicine, Cleveland, OH. hDepartment of Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil. Corresponding authors: Aline Silva de Miranda Laboratório de Imunofarmacologia Departamento de Bioquímica e Imunologia, ICB, UFMG Av. Antônio Carlos, 6627, Pampulha, Belo Horizonte 31270-901, Brazil. Tel.: +55 31 34092651; fax: +55 31 34092651. E-mail: mirandas.aline@gmail.com ' Abstract Miranda'et'al.,'2015'(In'preparation)' Cerebral malaria (CM) is a life-threatening complication of Plasmodium F.M.; Butterworth, A.E.; Roberts, M.B.; Dunne, D.W. High levels of TNF, soluble TNF receptors, soluble ICAM-1, and IFN-gamma, but low levels of IL-5, are associated with hepatosplenic disease in human schistosomiasis mansoni. J Immunol. 1998 Feb 15;160(4):1992-1999. 86 Nascimento, E.J.; Amorim, R.V.; Cavalcanti, A.; Alves, V.F.; Nakazawa, M.; Pereira, V.R.; Lucena-Silva, N. Assessment of a DNA vaccine encoding an anchoredglycosylphosphatidylinositol tegumental antigen complexed to protamine sulphate on immunoprotection against murine schistosomiasis. 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Desenvolvimento de vacinas recombinantes contra malária humana e teste in vivo em modelo murino
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