Cryptococcus neoformans is an opportunistic pathogenic fungus that causes several infections in humans, among these, cryptococcal meningitis is its most common manifestation, especially in immunocompromised patients, such as HIV carriers. Due to the few antifungal drugs available in the market, the low selective toxicity of the drugs, and the increasing appearance of resistant isolates, there is a need for new effective antifungal drugs that allow the use of lower dosages and with fewer side effects for the treatment of invasive fungal infections such as cryptococcosis. In this context, amino acid biosynthesis and uptake pathways have been the target of many studies, as they are determinants for virulence in C. neoformans. Regarding amino acid uptake, previous work from Laboratory of Microbial Interactions at UNIFESP (LIMic - UNIFESP), showed that the permeases Aap4 and Aap5 act as global and redundant transporters, being important for growth at 37ºC and in the presence of hydrogen peroxide. The sulfur amino acid biosynthesis pathway is also essential for growth, stress response, and virulence. Recently the regulation of sulfur amino acid biosynthesis has been clarified. The CYS3 gene is central to this pathway because it forms a complex with the catalytic and regulatory subunits of calcineurin (Cna1 and Cnb1, respectively) and with glycerol-3-phosphate phosphatase (Gpp2). Gpp2 in C. neoformans is involved with the response to low temperatures, membrane stress, cell wall stress, osmotic stress and alkaline stress. However, details about the relationship between Gpp2, calcineurin, osmotic stress, oxidative stress, and the sulfur amino acid biosynthesis pathway have not yet been clarified. The overall objective of this master's project is to establish the relationships between these elements and thus clarify important aspects of metabolism that affect virulence and pathogenicity in C. neoformans.
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