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Doctoral Thesis
DOI
10.11606/T.87.2018.tde-09022018-113614
Document
Author
Full name
Luís Guilherme Virgilio Fernandes
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2017
Supervisor
Committee
Nascimento, Ana Lucia Tabet Oller do (President)
Dagli, Maria Lucia Zaidan
Faria, Fernanda
Marques, Marilis do Valle
Ruiz, Rita de Cássia
Title in Portuguese
Caracterização da interação de Leptospira interrogans com o sistema protrombina/trombina e possíveis implicações na virulência.
Keywords in Portuguese
Leptospira
Coagulação
Disseminação
Hemorragia
Leptospirose
Abstract in Portuguese
Os mecanismos responsáveis pelas manifestações hemorrágicas durante a leptospirose severa ainda são pouco compreendidos. Este trabalho avaliou os efeitos diretos e indiretos das leptospiras sobre moléculas do sistema de coagulação. Foi verificado que leptospiras virulentas são eficientes em bloquear a atividade da enzima trombina por meio do sequestro de seu sítio de ligação ao substrato, gerando uma menor formação do coágulo de fibrina, acarretando em sangramento e consequente disseminação do patógeno para outros sítios de infecção. Foi mostrado também que a inflamação causada pela resposta imune contra as bactérias causa uma ativação da coagulação, muito provavelmente via expressão de Fator Tissular, o que ocasiona um consumo e consequente esgotamento dos fatores e inibidores de coagulação, culminando em hemorragia e formação de trombos, os quais podem levar à falência de órgãos. Estes resultados melhoram o entendimento da patogênese da leptospirose e podem favorecer o desenvolvimento de terapias para as manifestações hemorrágicas.
Title in English
Characterization of the interaction of Leptospira interrogans with prothrombin/thrombin system and possible implications in virulence.
Keywords in English
Leptospira
Coagulation
Dissemination
Hemorrhage
Leptospirosis
Abstract in English
The mechanisms responsible for the hemorrhagic manifestations during severe leptospirosis are still poorly understood. This work evaluated the direct and indirect effects of leptospires upon molecules of the coagulation system. It has been shown that virulent leptospires are effective in blocking the activity of the enzyme thrombin by sequestration of its substrate binding site, generating less fibrin clot formation, leading to bleeding and consequent dissemination of the pathogen to other sites of infection. It has also been shown that the inflammation caused by the immune response against the bacteria causes an activation of the coagulation, most probably via expression of Tissue Factor, which causes a consumption and consequent depletion of coagulation factors and inhibitors, culminating in hemorrhage and thrombus formation, which can lead to organ failure. These results improve the understanding of the pathogenesis of leptospirosis and may favor the development of therapies for hemorrhagic manifestations.
 
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Publishing Date
2018-02-09
 
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