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Doctoral Thesis
DOI
https://doi.org/10.11606/T.60.2014.tde-31102014-143222
Document
Author
Full name
Thalita Bachelli Riul
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2014
Supervisor
Committee
Baruffi, Marcelo Dias (President)
Bernardes, Emerson Soares
Albuquerque, Sérgio de
Alves Filho, José Carlos Farias
Valim, Yara Maria Lucisano
Title in Portuguese
Envolvimento de galectina-1 na infecção experimental aguda por Trypanosoma cruzi
Keywords in Portuguese
Galectina-1
imunorregulação
infecção
lectina
Trypanosoma cruzi
Abstract in Portuguese
A galectina-1 (Gal-1) é uma proteína que reconhece ?-galactosídeos e participa de vários processos biológicos, incluindo a modulação da resposta imunológica. Vários relatos da literatura reportam o potencial uso terapêutico da Gal-1 para doenças auto-imunes, inflamatórias e infecciosas. Entretanto, são escassos os relatos sobre o envolvimento da Gal-1 na infecção causada por Tripanosoma cruzi. Neste trabalho foi avaliada a participação da Gal-1 endógena e a administração de Gal-1 exógena na evolução da infecção aguda induzida experimentalmente por T. cruzi. Foram realizados experimentos in vivo e/ou in vitro com o uso de Gal-1 recombinante humana, camundongos C57BL/6 deficientes do gene da Gal-1 (Gal-1 KO, knock-out) ou do gene Toll Like Receptor 4 (TLR-4 KO, knock-out) e selvagens (WT, wild type), além de seus macrófagos. A forma de T. cruzi utilizada foi a tripomastigota da cepa Y. Os parâmetros analisados na caracterização do processo de infecção foram: i) parasitemia e sobrevivência de animais; ii) histopatologia do tecido cardíaco; iii) imunofenotipagem de leucócitos; iv) dosagem de citocinas; v) determinação de taxas de invasão e liberação de parasitas a partir de células infectadas; vi) produção de óxido nítrico por macrófagos. A Gal-1 e/ou anticorpos anti-glicopeptídeos miméticos de mucina de T. cruzi ligam-se à glicanas da superfície deste parasita e impedem sua invasão em fibroblastos e sua captura por macrófagos. O tratamento de macrófagos infectados com Gal-1 reduz a liberação de parasitas e aumenta a produção de óxido nítrico (NO) por um mecanismo, aparentemente, independente da sinalização via TLR-4. Os camundongos KO Gal-1 e os WT tratados com Gal-1 exógena apresentaram as menores taxas de parasitemia, sendo que os primeiros são mais resistentes à infecção aguda por T. cruzi. A ausência da Gal-1 endógena nos animais infectados provocou vários efeitos como a redução no infiltrado inflamatório e carga parasitária no tecido cardíaco, níveis séricos elevados de citocinas (IL-2, IL-4, IL-6, IL-10 e IL-17A), menor porcentagem de linfócitos T CD4+ e maior de T CD8+ no coração dos animais, aumento do influxo de neutrófilos na cavidade peritoneal e no coração. Com base nesse conjunto de resultados sugerimos que a ausência de Gal-1 endógena ou o tratamento de animais com Gal- 1 exógena promoveram perfis imunológicos (resposta inata e adaptativa) favorecedores da resolução da infecção experimental aguda por T. cruzi
Title in English
Involvement of galectin-1 on acute experimental Trypanosoma cruzi infection
Keywords in English
Galectin-1
immunoregulation
lectin
Trypanosoma cruzi infection
Abstract in English
Galectin-1 (Gal-1) is a protein that recognizes ?-galactosides and participates in many biological processes, including the modulation of the immune response. Several reports in the literature show the potential therapeutic use of Gal-1 to autoimmune, inflammatory and infectious diseases. However, there are few reports on the involvement of Gal-1 on infection caused by Trypanosoma cruzi. Here, we evaluated the involvement of endogenous Gal-1 and Gal-1 administration of exogenous in the development of acute experimental infection by T. cruzi. Recombinant human Gal-1, C57BL/6 mice deficient for Gal-1 gene (Gal-1 KO, knockout) or for Toll like receptor 4 gene (TLR-4 KO, knock-out) or C57BL/6 wild type mice (WT), and macrophages from these animals were used in experiments in vivo and / or in vitro. The form of T. cruzi used in this work was trypomastigotes from Y strain. The analyzed parameters characterizing the process of infection were: i) parasitemia and survival of animals; ii) histopathology of cardiac tissue; iii) leucocyte immunophenotyping; iv) cytokine assay; v) determination of invasion and release rates of parasites from infected cells; vi) nitric oxide production by macrophages. The Gal-1 and / or antibodies anti- glycopeptides that mimics T. cruzi mucin bind to glycans on the surface of this parasite and prevent invasion of the parasite in fibroblasts and its capture by macrophages. Treatment of infected macrophages with Gal-1 promotes a lower release of parasites and increased production of nitric oxide (NO) by these phagocytes, and this production of NO is independent of TLR-4 signaling pathway. The Gal-1 KO mice and WT mice treated with exogenous Gal-1 had the lowest rates of parasitemia and the first group is more resistant to acute infection with T. cruzi. The absence of endogenous Gal-1 in infected animals caused various effects such as a reduction in the inflammatory infiltrate and the parasite load in the cardiac tissue, elevated serum levels of cytokines (IL-2, IL-4, IL-6, IL-10 and IL- 17A), a lower percentage of T CD4+ and increased T CD8+ the hearts of animals, increased influx of neutrophils into the peritoneal cavity and heart tissue. Based on this set of results we suggest that the absence of endogenous Gal-1 or treatment of animals with exogenous Gal-1 promoted immunological profiles (innate and adaptive response) favoring the resolution of acute experimental T. cruzi infection.
 
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Publishing Date
2014-11-11
 
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