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Doctoral Thesis
DOI
10.11606/T.42.2014.tde-15122014-100724
Document
Author
Full name
Mónica Marcela Castiblanco Valencia
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2014
Supervisor
Committee
Isaac, Lourdes (President)
Carvalho, Enéas de
Ferreira, Luis Carlos de Souza
Piazza, Roxane Maria Fontes
Seguro, Antonio Carlos
Title in Portuguese
Interação de proteínas de membrana de Leptospira com os reguladores Fator H e C4BP do sistema complemento humano.
Keywords in Portuguese
Leptospira
C4BP
Evasão imune
Fator H
Proteínas Lig
Sistema complemento
Abstract in Portuguese
Diferentes mecanismos têm sido mostrados por estar envolvidos na evasão à morte mediada por complemento. Neste estudo, demonstramos que a aquisição do FH pela Leptospira é crucial para a sobrevivência das bactérias no soro e que estas espiroquetas interagem com FH, FHL-1, FHR-1 e C4BP. Nós também demonstramos que a ligação à estes reguladores é mediada pelas proteínas leptospiral immunoglobulin-like (Lig). FH se liga as proteínas Lig via short consensus repeat (SCR) principalmente pelos domínios 5 e 20. Ensaios de competição sugerem que FH e C4BP têm sítios de ligação diferentes nas proteínas Lig. Além disso, FH e C4BP ligados nas proteínas Lig mantêm a atividade de cofator, mediando a degradação de C3b e C4b pelo FI. Nós demonstramos que a aquisição de FH e C4BP pela L. biflexa transgênica para LigA e LigB exercem um papel de proteção na sobrevida destas bactérias. Análise por citometria de fluxo também confirmaram a capacidade das leptospiras transgênicas para controlar a deposição de C3, C4 e MAC. As proteínas Lig também foram capazes de ligar plasminogênio, o qual foi ativado em plasmina e esta enzima foi capaz de degradar fibrinogénio, C3b e C5. Estas clivagens inativam C3b e C5, evitando a progressão da cascata, e bloqueando as três vias de complemento.
Title in English
Interaction of Leptospira membrane proteins with human complement regulators Factor H and C4BP.
Keywords in English
Leptospira
C4BP
Complement system
Factor H
Immune evasion
Lig proteins
Abstract in English
Different mechanisms have been shown to be involved in evasion of complement-mediated killing. In this study, we demonstrate that acquisition of FH on the Leptospira surface is crucial for bacterial survival in the serum and that these spirochetes interact with FH, FHL-1, FHR-1 and C4BP. We also demonstrate that binding to these regulators is mediated by leptospiral immunoglobulin-like (Lig) proteins. FH binds to Lig proteins via short consensus repeat (SCR) domains 5 and 20. Competition assays suggest that FH and C4BP have distinct binding sites on Lig proteins. Moreover, FH and C4BP bound to immobilized Ligs display cofactor activity, mediating C3b and C4b degradation by FI. We demonstrated that acquisition of FH and C4BP by the LigA and LigB transformed L. biflexa have the protective role, being crucial by bacterial survival. Analysis by Cytometer fluid also confirmed the ability of L. biflexa expressing LigA and LiB to controller the deposition of C3, C4 and MAC. Lig proteins were able to bind plasminogen, which was activated to plasmin and this enzyme was able to degrade the fibrinogen, C3b and C5. These cleavages inactivate C3b and C5, preventing progression of the complement cascade and blocking the three complement pathways.
 
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Release Date
2016-12-15
Publishing Date
2014-12-16
 
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