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Molecular characterization of htlA and fhdA transcription factors of human pathogenic fungus Aspergillus fumigatus

Grant number: 16/22062-6
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2017
Effective date (End): February 28, 2019
Field of knowledge:Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Gustavo Henrique Goldman
Grantee:Jéssica Chiaratto
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Aspergillus fumigatus is a saprophytic fungus and one of the main human pathogenic fungi. Its conidia are inhaled and reach the lungs where they become active and germinate, resulting in a condition known as aspergillosis. Aspergillosis has a higher risk for immunosuppressed patients. Echinocandins, such as caspofungin, are antifungal agents whose target is the fungal cell wall. These agents reduce the total concentration of 1,3-²-D-glucan in the cell wall by inhibiting the activity of ²-1,3-glucan synthase. Interestingly, the inhibition of the synthesis of a polysaccharide type present in the cell wall can lead to increase of others, which presumably represents a defense mechanism that allows the cell to escape from the lethality. The paradoxical effect, is the result of attenuation of the activity of echinocandins in high concentrations. However, caspofungin has an excellent safety profile and have increasingly being used as second-line therapy against fungi. Echinocandins are capable of inducing a set of genes related to protein kinase C pathway that maintains the integrity of the cell wall. Moreover, the compensatory increase of chitin is coordinated by PKC, and calcineurin HOG. Inhibition of the synthesis of components of cell appears through antifungal drugs may be an important target against infections caused by Aspergillus fumigatus. Thus, we used a library of 395 deleted transcription factors in order to find transcription factors related to caspofungin sensitivity and two mutants, ”hltA (Afu5g10620) and ”fhdA (Afu7g05440) were selected. Preliminary results of the phenotypic analysis in solid minimal medium showed a higher sensitivity of both null mutants to high concentrations of caspofungin (16 mg / mL). In the presence of 5 mM EGTA, 0.25 mg / mL caspofungin and 44 ° C, ”fhdA the mutant was more sensitive than wild type. In the same conditions of 0.25 mg / ml of caspofungin and 44 ° C, the ”hltA mutant also showed to be more sensitive. Further studies are needed to confirm the role of these transcription factors in the adaptive response of the fungus to caspofungin. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DE CASTRO, PATRICIA ALVES; VALERO, CLARA; CHIARATTO, JESSICA; COLABARDINI, ANA CRISTINA; PARDESHI, LAKHANSING; SILVA, LILIAN PEREIRA; ALMEIDA, FAUSTO; ROCHA, MARINA CAMPOS; SILVA, ROBERTO NASCIMENTO; MALAVAZI, IRAN; DU, WENYUE; DYER, PAUL S.; BROCK, MATTHIAS; LOURES, FLAVIO VIEIRA; WONG, KOON HO; GOLDMAN, GUSTAVO H. Novel Biological Functions of the NsdC Transcription Factor in Aspergillus fumigatus. MBIO, v. 12, n. 1 JAN-FEB 2021. Web of Science Citations: 0.
DE CASTRO, PATRICIA ALVES; COLABARDINI, ANA CRISTINA; MANFIOLLI, ADRIANA OLIVEIRA; CHIARATTO, JESSICA; SILVA, LILIAN PEREIRA; MATTOS, ELICIANE CEVOLANI; PALMISANO, GIUSEPPE; ALMEIDA, FAUSTO; PERSINOTI, GABRIELA FELIX; ANNICK RIES, LAURE NICOLAS; MELLADO, LAURA; ROCHA, MARINA CAMPOS; BROMLEY, MICHAEL; SILVA, ROBERTO NASCIMENTO; DE SOUZA, GABRIEL SCALINI; LOURES, FLAVIO VIEIRA; MALAVAZI, IRAN; BROWN, NEIL ANDREW; GOLDMAN, GUSTAVO H. Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance. PLOS GENETICS, v. 15, n. 12 DEC 2019. Web of Science Citations: 0.

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