Amino Acid Permeases and Virulence in Cryptococcus neoformans

Amino Acid Permeases and Virulence in Cryptococcus neoformans

Author Martho, Kevin Felipe Cruz Autor UNIFESP Google Scholar
Melo, Amanda Teixeira de Autor UNIFESP Google Scholar
Fernandes Takahashi, Juliana Possato Google Scholar
Guerra, Juliana Mariotti Google Scholar
da Silva Santos, Dayane Cristina Google Scholar
Purisco, Sonia Ueda Google Scholar
Carvalho Melhem, Marcia de Souza Google Scholar
Fazioli, Raquel dos Anjos Google Scholar
Phanord, Clerlune Autor UNIFESP Google Scholar
Sartorelli, Patricia Autor UNIFESP Google Scholar
Vallim, Marcelo Afonso Autor UNIFESP Google Scholar
Pascon, Renata Castiglioni Autor UNIFESP Google Scholar
Abstract Fungal opportunistic pathogens colonize various environments, from plants and wood to human and animal tissue. Regarding human pathogens, one great challenge during contrasting niche occupation is the adaptation to different conditions, such as temperature, osmolarity, salinity, pressure, oxidative stress and nutritional availability, which may constitute sources of stress that need to be tolerated and overcome. As an opportunistic pathogen, C. neoformans faces exactly these situations during the transition from the environment to the human host, encountering nutritional constraints. Our previous and current research on amino acid biosynthetic pathways indicates that amino acid permeases are regulated by the presence of the amino acids, nitrogen and temperature. Saccharomyces cerevisiae and Candida albicans have twenty-four and twenty-seven genes encoding amino acid permeases, respectively

conversely, they are scarce in number in Basidiomycetes (C. neoformans, Coprinopsis cinerea and Ustilago maydis), where nine to ten permease genes can be found depending on the species. In this study, we have demonstrated that two amino acid permeases are essential for virulence in C. neoformans. Our data showed that C. neoformans uses two global and redundant amino acid permeases, Aap4 and Aap5 to respond correctly to thermal and oxidative stress. Double deletion of these permeases causes growth arrest in C. neoformans at 37 degrees C and in the presence of hydrogen peroxide. The inability to uptake amino acid at a higher temperature and under oxidative stress also led to virulence attenuation in vivo. Our data showed that thermosensitivity caused by the lack of permeases Aap4 and Aap5 can be remedied by alkaline conditions (higher pH) and salinity. Permeases Aap4 and Aap5 are also required during fluconazole stress and they are the target of the plant secondary metabolite eugenol, a potent antifungal inhibitor that targets amino acid permeases. In summary, our work unravels (i) interesting physiological property of C. neoformans regarding its amino acid uptake system

(ii) an important aspect of virulence, which is the need for amino acid permeases during thermal and oxidative stress resistance and, hence, host invasion and colonization

and (iii) provides a convenient prototype for antifungal development, which are the amino acid permeases Aap4/Aap5 and their inhibitor.
xmlui.dri2xhtml.METS-1.0.item-coverage San Francisco
Language English
Sponsor Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
Grant number FAPESP: 2011/51298-4
FAPESP: 2015/04400-9
Date 2016
Published in Plos One. San Francisco, v. 11, n. 10, p. -, 2016.
ISSN 1932-6203 (Sherpa/Romeo, impact factor)
Publisher Public Library Science
Extent -
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000385553100065

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