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Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2020.tde-16122019-161916
Document
Author
Full name
Leandro Carvalho Dantas Breda
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2019
Supervisor
Committee
Almeida, Sandro Rogerio de (President)
Campa, Ana
Rodrigues, Anderson Messias
Taborda, Carlos Pelleschi
Title in Portuguese
O papel dos neutrófilos e dos receptores TLR-2 e TLR-4 na cromoblastomicose experimental em infecção por Fonsecaea pedrosoi
Keywords in Portuguese
F. pedrosoi
Cromoblastomicose
MDSCs
Neutrofilo
Abstract in Portuguese
A cromoblastomicose e uma micose subcutanea cronica e progressiva causada principalmente pelo fungo Fonsecaea pedrosoi. As infeccoes estabelecidas podem desenvolver lesoes crostosas e exsudativas com formacao de granulomas,compostos principalmente por macrofagos e neutrofilos. O F. pedrosoi e um fungodimorfico e pode ser encontrado na forma de micelios e conidios (fase saprofita) e na forma de esclerotica (fase infecciosa). A forma esclerotica e altamente resistente aos mecanismos imunologicos do hospedeiro permitindo, portanto, a instalacao e progressao da doenca. Poucos sao os trabalhos que observaram o papel dos neutrofilos - importante celula no combate a infeccoes fungicas - na eliminacao do F. pedrosoi. Neste presente trabalho nos verificamos a importancia dos neutrófilos murinos na eliminacao in vitro das hifas e conidios de F. pedrosoi. Nossos dados indicam que a fagocitose e a producao de especies reativas de oxigenio (ROS) sobre conidios de F. pedrosoi sao dependentes dos receptores TLR-2 e TLR-4 e sao essenciais na eliminacao dos conidios, enquanto a eliminacao das hifas ocorre por meio da liberacao das NETs, que e um mecanismo independente de TLR-2 e TLR-4 e ROS. Nos tambem verificamos que os receptores TLR-2 e TLR-4 são importantes para a migracao dos neutrofilos ate o sitio infeccioso in vivo e também são importantes na contencao e eliminacao do fungo nos camundongos. Usando modelo de animais neutropenicos nos verificamos que na ausencia de neutrófilos acarreta numa maior proliferacao de linfocitos T bem como uma menor producao de anticorpos contra o fungo e menor carga fungicas na baco e figado dos animais. Deste modo, nossos dados indicam que o fungo F. pedrosoi apresenta a capacidade de modular a resposta imune do hospedeiro, levando ao surgimento de uma subpopulacao regulatorio de neutrofilos, denominados de N2 ou MDSCs (do inglês Myeloid Derived Suppressor Cells) favorecendo, portanto, a cronicidade da cromoblastomicose.
Title in English
The role of neutrophils and Toll Like Receptors 2 and 4 in experimental Chromoblastomycosis by F. pedrosoi
Keywords in English
Chromoblastomycosis
F. pedrosoi
MDSCs
Neutrophil
Abstract in English
Chromoblastomycosis is a chronic and progressive subcutaneous mycosis caused mainly by the fungus Fonsecaea pedrosoi. The infection is characterized by erythematous papules and the histological sections composed of an external layer of fibrous tissue and an internal layer of thick granulomatous inflammatory tissue containing mainly macrophages and Neutrophils. F. pedrosoi is a dimorphic fungus and can be found in mycelium and conidial forms (saprophyte phase) or sclerotic bodies (infection phase) - characterized by spherical bodies with thickness and pigmented cell wall. Currently, little is known about neutrophils functions in chromoblastomycosis. Several groups have been studying the role of the innate and adaptive immune system in infection by F. pedrosoi, however few studies have been focusing on the neutrophils role in this infection. In this study we verified the importance of murine neutrophils in F. pedrosoi conidia and hyphae killing. Our results demonstrate that phagocytosis and reactive oxygen species (ROS) over conidia infection is TLR-2 and TLR-4-dependent and are essentials to conidia killing. Meanwhile, hyphae killing occurs by NETs formation, in a TLR-2, TLR-4 and ROS-independent manner. The TLR-2 and TLR-4 are also important in neutrophil migration to the infection site, as well as in contain and eliminate the infection in vivo. Using neutropenic animals, we verified a higher Tcell proliferation and lower specific-antibody production and fungal load in targetorgans in the absent of neutrophils. Therefore, our data indicate that F. pedrosoi has the ability to modulate host immune response, leading to the development of anti-inflammatory neutrophils, called N2 or MDSCs (Myeloid Derived Suppressor Cells), that promotes the chronicity of the chromoblastomycosis disease.
 
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Release Date
2021-12-15
Publishing Date
2020-02-14
 
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