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The role of a retrograde regulation in Aspergillus fumigatus pathogenicity/virulence

Grant number: 13/23807-7
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2014
Effective date (End): August 31, 2015
Field of knowledge:Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
Principal Investigator:Gustavo Henrique Goldman
Grantee:Elodie Marie-Jeanne Bovier
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

To colonize, infect, and invade a host and cause disease, A. fumigatus has to adapt its metabolism to diverse host microenvironments. The aim of this project is to explore the link between A. fumigatus pathogenicity/virulence and the retrograde regulation responsible for both the induction of an alternative respiratory pathway (via the AOX, a non proton pumping enzyme that bypass the cytochrome pathway) and the induction of the gluconeogenesis. There is evidence of a conserved retrograde regulation involved in the reprogramming of nuclear gene expression in response to a mitochondrial impairment that could be involved in a metabolic adaptation to the host environment: in the filamentous ascomycetes, Neurospora crassa, Podospora anserina and Aspergillus nidulans. Recent data have shown that two zinc cluster transcription factors, from the Zn2Cys6 family, highly conserved in these three species, are required for the expression of the aox gene and for regulating the two key enzymes specific for gluconeogenesis: phosphoenolpyruvate carboxykinase (PCK) and fructose-1,6-biphosphatase (FBP). In A. fumigatus, this transcription factors are AcuM and Afu2g05830. Only AcuM has been studied at the moment and the study shows that it regulates both iron acquisition and gluconeogenesis. AcuM is also involved in resistance to macrophage killing and it is essential for maximal virulence. Moreover, several studies in A. fumigatus have shown that the AOX is involved in the hypoxia adaptation, the resistance to oxidative stress and the resistance to macrophage killing even if it doesn't present a modification of its virulence. Another potential target had a link with pathogenicity/virulence: the flavohemoglobin, Afu4g03410 (that is a target of the AcuK homogue in P. anserina), is up regulated in response to hypoxia and the deletion of the corresponding genes of the NO-detoxifying flavohemoproteins in the pathogenic yeasts C. neoformans and C. albicans led to attenuated virulence .To explore the link between A. fumigatus pathogenicity/virulence and the regulation of the retrograde response, we will first focus on the retrograde regulation itself: 1) the conserved actors (AcuM and Afu2g05830) by constructing and analysising deleted strains (ROS and macrophage susceptibility assays and in vivo virulence assays), 2) the targets (aox, the flavohemoglobin fhb, the gluconeogenic genes acuF and fbp1 and the transcription factors involved in iron acquisition, sreA and hapX) and their condition of activation thorugh qPCR experiments in the wild type and deleted strains under diferent conditions (respiratory chain impairment, gluconeogenic carbon sources, iron limited environment and hypoxia), 3) microarray analysis is also planned to identify the targets of the transcription factors under gluconeogenic environment and hypoxia. Those data will be compared to "omics" data available. This project will permit a better understanding of the transcriptional adaptation of A. fumigatus needed for its pathogenicity/virulence.