Amino acid permeases in Cryptococcus neoformans are required for high temperature growth and virulence; and are regulated by Ras signaling

Autor(es)

Calvete, Crislaine Lambiase ^{[1, 2]} ; Martho, Kevin Felipe ^[1] ; Felizardo, Gabrielle ^[1] ; Paes, Alexandre ^[1] ; Nunes, Joao Miguel ^[1] ; Ferreira, Camila Oliveira ^[1] ; Vallim, Marcelo A. ^[1] ; Pascon, Renata C. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Biol Sci, Campus Diadema, Diadema, SP - Brazil

^[2] Univ Sao Paulo, Biotechnol Grad Program, Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 14, n. 1 JAN 25 2019.
• Citações Web of Science: 1

Resumo

Cryptococcosis is an Invasive Fungal Infection (IFI) caused by Cryptococcus neoformans, mainly in immunocompromised patients. Therapeutic failure due to pathogen drug resistance, treatment inconstancy and few antifungal options is a problem. The study of amino acid biosynthesis and uptake represents an opportunity to explore possible development of novel antifungals. C. neoformans has 10 amino acids permeases, two of them (Aap3 and Aap7) not expressed at the conditions tested, and five were studied previously (Aap2, Aap4, Aap5, Mup1 and Mup3). Our previous results showed that Aap4 and Aap5 are major permeases with overlapping functions. The aap4 Delta/aap5 Delta double mutant fails to grow in amino acids as sole nitrogen source and is avirulent in animal model. Here, we deleted the remaining amino acid permeases (AAP1, AAP6, AAP8) that showed gene expression modulation by nutritional condition and created a double mutant (aap1 Delta/aap2 Delta). We studied the virulence attributes of these mutants and explored the regulatory mechanism behind amino acid uptake in C. neoformans. The aap1 Delta/aap2 Delta strain had reduced growth at 37 degrees C in L-amino acids, reduced capsule production and was hypovirulent in the Galleria mellonella animal model. Our data, along with previous studies, (i) complement the analysis for all 10 amino acid permeases mutants, (ii) corroborate the idea that these transporters behave as global permeases, (iii) are required during heat and nutritional stress, and (iv) are important for virulence. Our study also indicates a new possible link between Ras1 signaling and amino acids uptake. (AU)

• Processo FAPESP: 16/23890-0 - Identificação de alvos moleculares em Cryptococcus neoformans e a importância da permease de aminoácidos AAP1 para os fatores de virulência
• Beneficiário: João Miguel Alves Nunes
• Linha de fomento: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 15/04400-9 - O papel da autofagia no crescimento a alta temperatura (37°C) e virulência em Cryptococcus neorformans
• Beneficiário: Marcelo Afonso Vallim
• Linha de fomento: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/14542-8 - Caracterização genética dos elementos regulatórios que controlam a biossíntese e a assimilação de aminoácidos e o seu papel na virulência de Cryptococcus neoformans
• Beneficiário: Renata Castiglioni Pascon
• Linha de fomento: Auxílio à Pesquisa - Regular