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PLoS One
2019 Jan 01;141:e0211393. doi: 10.1371/journal.pone.0211393.
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Amino acid permeases in Cryptococcus neoformans are required for high temperature growth and virulence; and are regulated by Ras signaling.
Calvete CL
,
Martho KF
,
Felizardo G
,
Paes A
,
Nunes JM
,
Ferreira CO
,
Vallim MA
,
Pascon RC
.
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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 aap4Δ/aap5Δ 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 (aap1Δ/aap2Δ). We studied the virulence attributes of these mutants and explored the regulatory mechanism behind amino acid uptake in C. neoformans. The aap1Δ/aap2Δ strain had reduced growth at 37°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.
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Fig 1. Amino acid sequence alignment.Conserved residues at transmembrane one (TM1) of C. neoformans and H. sapiens permeases of the APC family. The red inverted triangles represent glycine residues that are known to be invariable and essential for amino acid affinity and binding in S. cerevisiae APC permeases.
Fig 3. Animal model of infection in G. mellonella.The larvae were inoculated with the wild type (H99), single mutants (aap6Δ and aap8Δ) or double deletion (aap1Δ/aap2Δ) at 37°C for 8 days. Survival was followed during the course of the infection. Mutants aap8Δ and aap1Δ/aap2Δ were hypovirulent when compared to wild type H99 (**** and ***, respectively). PBS is a negative control.
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