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Cryptococcus neoformans and the relationship among virulence, sulfur metabolism and osmotic and oxidative stresses


The UNIFESP Microbial Interaction Laboratory (LIMic) research group has a line of research that studies the genetic mechanisms that control the response to nutritional stress in fungi, which is essential for pathogenesis. In addition, it is part of this line of research to prospect for new inhibitors that have antifungal potential. Treatment against eukaryotic pathogens is difficult as there are few drug options and low selective toxicity. Therefore, this study seeks new therapeutic strategies, which depend on the identification of new molecular targets that may be useful for the development of drugs against deep mycoses. Researchers in this group use the opportunistic yeast Cryptococcus neoformans as a study model. Moreover, this pathogen is of great medical importance because it causes fungal meningitis in immunocompromised individuals and is the leading cause of fatalities in AIDS patients along with tuberculosis. Over the past seven years, we have shown that biosynthesis and amino acid uptake are essential processes for virulence in C. neoformans and are very different between fungi and animals. Also, through the use of genetic engineering, cell biology, proteomics and transcriptomics techniques, our data showed that (i) amino acid uptake by permeases is regulated by the Ras1 signaling pathway; (ii) sulfur uptake and sulfur amino acid biosynthesis is regulated by the transcription factor Cys3 together with the Calcineurin complex, revealing a novel relationship in the literature between these genetic elements, which are essential for virulence and pathogenicity. Moreover, our previous studies have shown that (iii) there is a link between sulfur metabolism, osmotic balance, guaranteed by glycerol biosynthesis, and oxidative stress. This latest finding has opened a new research line that needs to be developed, as it places sulfur metabolism at the center of processes relevant to virulence, such as resistance to stresses found in the host. Therefore the aims of this work are (1) to deepen the studies on the regulatory relationships previously observed between the transcription factor Cys3 and ATP sulphorylase Met3, the latter being very distinct structure between fungi, plants and animals; (2) expand the understanding of the mechanism of calcineurin regulation on the sulfur assimilation pathway and osmotic stress; (3) develop studies on the role of Gpp2 in sulfur uptake and sulfur amino acid biosynthesis, as well as in the glutathione biosynthesis pathway and in the response to oxidative stress; (4) It is part of this work to test the antifungal activity of methionine analogs and coumaric acid derivatives on growth and melanization, respectively. This study is expected to reflect new knowledge about the response to nutritional stress and new targets for the treatment of cryptococcosis and other fungal diseases. (AU)

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