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Thèse de Doctorat
DOI
10.11606/T.42.2014.tde-27112014-094144
Document
Auteur
Nom complet
Tatiana Rodrigues Fraga
Unité de l'USP
Domain de Connaissance
Date de Soutenance
Editeur
São Paulo, 2014
Directeur
Jury
Isaac, Lourdes (Président)
Carvalho, Cristiane Rodrigues Guzzo
Portaro, Fernanda Calheta Vieira
Reis, Edimara da Silva
Silva, Aline Maria da
Titre en portugais
Identificação de proteases de Leptospira envolvidas com mecanismos de escape do sistema complemento humano.
Mots-clés en portugais
Evasão Imune
Leptospirose
Proteases
Sistema complemento
Resumé en portugais
A leptospirose é uma zoonose causada por leptospiras patogênicas. Para estabelecer a infecção, estas bactérias desenvolveram estratégias de escape ao sistema complemento. Neste trabalho demonstramos que o sobrenadante de cultura de leptospiras patogênicas é capaz de inibir as três vias do complemento. Observamos que esse sobrenadante possui atividade proteolítica sobre C3, C3b e iC3b, além do FB (via alternativa), C2 e C4b (via clássica e das lectinas). As proteínas C3, C4, C2 e FB também foram clivadas quando soro humano normal (SHN) foi utilizado como fonte de complemento. Demonstramos que as proteases atuam em conjunto com os reguladores do hospedeiro Fator I e Fator H na clivagem de C3b. As clivagens foram inibidas pela 1,10-fenantrolina, sugerindo a participação de metaloproteases. Metaloproteases de leptospira da família das termolisinas foram produzidas como proteínas recombinantes e clivaram C3 no SHN. Concluímos que proteases de leptospiras patogênicas podem desativar moléculas do complemento e são potencias alvos para novas terapias em leptospirose.
Titre en anglais
Identification of leptospiral proteases involved in immune evasion mechanisms from the human complement system.
Mots-clés en anglais
Complement system
Immune evasion
Leptospirosis
Proteases
Resumé en anglais
Leptospirosis is a zoonotic disease caused by pathogenic Leptospira. To establish the infection, these bacteria have developed strategies to escape the complement system. In this work, we demonstrate that culture supernatant from pathogenic Leptospira is capable of inhibiting the three complement pathways. We observe that this supernatant possess proteolytic activity under C3, C3b and iC3b, FB (alternative pathway), C2 and C4b (classical and lectin pathways). The proteins C3, C4, C2 and FB were also cleaved when normal human serum (NHS) was used as a source of complement. We demonstrate that these proteases act together with the host regulators Factor I and Factor H in C3b cleavage. The cleavages were inhibited by 1,10-phenanthroline, suggesting the involvement of metalloproteinases. Leptospira metalloproteinases from the thermolysin family were produced as recombinant proteins and cleaved C3 in NHS. We concluded that proteases from pathogenic Leptospira can inactivate complement molecules and are potential targets for new therapies in leptospirosis.
 
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Date de Libération
2018-11-28
Date de Publication
2014-11-29
 
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