| Grant number: | 16/14542-8 |
| Support type: | Regular Research Grants |
| Duration: | October 01, 2016 - June 30, 2019 |
| Field of knowledge: | Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms |
| Principal Investigator: | Renata Castiglioni Pascon |
| Grantee: | Renata Castiglioni Pascon |
| Home Institution: | Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil |
Abstract
C. neoformans is an opportunistic fungal pathogen of great medical importance because it affects immunocompromised individuals. Treatment against eukaryotic pathogens is difficult because there are few options of antifungal drugs and low selective toxicity. As a result, there is an effort of the scientific community to better understand the differences between pathogens and hosts in relation to the mechanisms that control essential biological processes, in order to find new useful drug targets. Studies on synthesis, uptake and recycling of amino acids have been shown to be very promising. Our previous studies have shown that the molecular mechanisms of biosynthesis and uptake of amino acids are (i) essential for virulence in C. neoformans, (ii) are very different from fungi and animals, as there is evidence of (iii) distinction of these processes among the ascomycetes and basidiomycetes. Still, our data showed that elements linked to the biosynthesis (enzymes) and amino acid uptake (permeases) are the targets of inhibitors of fungal growth. However, little is known about the regulation of this important nutritional process in C. neoformans and Basidiomycetes in general. In S. cerevisiae three regulatory pathways governing the acquisition of such nutrient: GAAC (Global Amino Acid Control), SPS-sensing and catabolic repression by the preferred source of nitrogen (NCR). In C. neoformans, NCR was reported by other laboratories and our published data demonstrate that it controls the genes related to the biosynthesis and uptake of amino acids. However, our experiments indicate that two other mechanisms (GAAC and SPS-sensing) can act in C. neoformans, though with different genetic elements. Further, recently we identified that uptake of amino acids is essential for the resistance to thermal and oxidative stress, conditions which are found in the host, and therefore are essential for virulence. The proposed work aims to explore the genetic basis that regulate the biosynthesis and uptake of amino acids using two approaches: (i) study the regulation based on the similar mechanisms known in ascomycetes (GAAC and SPS sensing) and (ii) explore the regulatory relationships between heat stress and amino acid uptake, a phenomenon detected by our study, and evaluate how all these regulatory processes affect the virulence of C. neoformans. We expect (i) to know the mechanisms governing the uptake of amino acids in C. neoformans and basidiomycetes and (ii) in this study reflect new targets for treatment options against Cryptococcus and other fungal diseases. (AU)