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Master's Dissertation
DOI
https://doi.org/10.11606/D.17.2021.tde-08092021-113412
Document
Author
Full name
Ailton Pereira da Costa Filho
Institute/School/College
Knowledge Area
Date of Defense
Published
Ribeirão Preto, 2021
Supervisor
Committee
Goldman, Gustavo Henrique (President)
Nimrichter, Leonardo
Silva, Livia Kmetzsch Rosa e
Title in Portuguese
Caracterização molecular de um receptor acoplado a uma proteína G (GPCR) de Aspergillus fumigatus
Keywords in Portuguese
Aspergillus fumigatus
GprJ
GprM
Via de integridade de parede celular
Abstract in Portuguese
O Aspergillus fumigatus é um fungo oportunista de potencial letalidade. Devido ao reduzido tamanho de seus conídios, os pulmões são facilmente atingidos. Em meio a temperatura propicia, o fungo germina e pode causar danos ao hospedeiro. Indivíduos imunodeprimidos são hospedeiros potenciais visto que o sistema imunológico não é capaz de eliminá-lo nas fases iniciais da infecção e se tornam vítimas de aspergilose. Através de vias de transdução de sinais, fungos oportunistas como o A. fumigatus percebem o ambiente, modulam seu metabolismo de modo a evadir o sistema imunológico do hospedeiro. As GPCRs são exemplos de vias transdutoras de sinais com pelo menos 15 prováveis GPCRs identificadas em A. fumigatus, as quais já foram identificadas como prováveis receptoras de feromônios e AMPc e sensores de carbono e nitrogênio. Recentemente nosso laboratório caracterizou GprM e GprJ como moduladores importantes da produção de melanina e da proteína quinase ativada por mitógenos (MAPK) MpkA que controla a via de integridade da parede celular em A. fumigatus. O conteúdo de açúcares nas paredes celulares foi variável entre os mutantes e a cepa selvagem, sendo importante mencionar que o transcriptoma mostrou que gprM e gprJ regulam negativamente genes responsáveis pela produção dos metabólitos secundários fumagilina, piripiropeno, fumigaclavina C, fumiquinazolina e fumitremorgina. Foi observado ainda que a superexpressão de gprM modula o fator de transcrição asgA, o qual se mostrou à jusante da sinalização de GprM e MpkA. Os mutantes ΔgprM e ΔgprJ apresentam virulência reduzida em larvas de Galleria mellonella que se apresenta como modelo de estudo para a aspergilose invasiva. Portanto, a caracterização de genes e vias relacionadas em A. fumigatus fornece conhecimento dos mecanismos de virulência e pode beneficiar indivíduos imunocomprometidos.
Title in English
Molecular characterization of a receptor coupled to a G protein (GPCR) of Aspergillus fumigatus
Keywords in English
Aspergillus fumigatus
Cell wall integrity pathway
GprJ
GprM
Abstract in English
Aspergillus fumigatus is an opportunistic fungus with potential lethality. Due to the small size of its conidia, the lungs are easily reached. In propitious temperature, the fungus germinates and can cause damage to the host. Immunocompromised individuals are potential hosts because the immune system is unable to eliminate conidia in early stages of infection and consequently become victims of aspergillosis. Through signal transduction pathways, opportunistic fungi like A. fumigatus perceive the environment, modulate their metabolism in order to evade the host's immune system. GPCRs are examples of signal transducers pathways with at least 15 putative GPCRs identified in A. fumigatus, which have already been identified as likely pheromone and cAMP receptors and carbon and nitrogen sensors. Recently, our laboratory characterized GprM and GprJ as important modulators of melanin production and the Cell Wall Integrity Pathway, in addition to the protein kinase MpkA. The sugar content in the cell walls was variable between the mutants and the wild-type strain, moreover the transcriptome showed that gprM and gprJ negatively regulate genes responsible for the production of secondary metabolites: fumagillin, pyripyropene, fumigaclavin C, fumiquinazoline and fumitremorgin. It was also observed that the overexpression of gprM modulates the transcription factor asgA, which was shown to be downstream of gprM and MpkA signaling. The ΔgprM and ΔgprJ mutants have shown reduced virulence in Galleria mellonella larvae, which consists as a study model for invasive aspergillosis. Therefore, the characterization of genes and related pathways in A. fumigatus provides knowledge of virulence mechanisms and can benefit immunocompromised individuals.
 
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Publishing Date
2021-10-01
 
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