The role of mitogen-activated protein kinase (MPKA) MpkA in regulating gliotoxin production in Aspergillus fumigatus.

• Grant number: 16/12948-7
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: November 01, 2016
• End date: January 03, 2022
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Gustavo Henrique Goldman
• Grantee: Patrícia Alves de Castro Silva
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 16/07870-9 - The influence of mitogen activated protein kinases (MAPK) on the expression of genetic determinants important for Aspergillus fumigatus virulence, AP.TEM
• Associated scholarship(s): 17/07732-8 - Chromatin Immunoprecipitation-DNA sequencing (ChIP-seq) aiming to identify genes regulated by the bZIP ZipD transcription factor in Aspergillus fumigatus, BE.EP.PD

Abstract

Aspergillus fumigatus is a filamentous fungus and an important opportunistic pathogen and mammalian allergen. It is responsible for approximately 65% of all invasive fungal infections in humans, and also the main species related to lung infections. The importance of infections by this fungus is reflected by a series of reviews that have been published in recent years on its biology and pathology, in addition to a great effort that has been made to identify the virulence factors of this pathogen. Among these factors, secondary metabolites stand out, once they are secreted during infection, generally considered to be the front line virulence factors, and cause suppression of the host's immune functions. Gliotoxin (GT) is the main, most abundant and most potent secondary metabolite produced by A. fumigatus. It exhibits a diverse range of biological effects, including a potent intracellular redox activity, which leads to an imbalance in homeostasis and severe oxidative stress in human cells. The regulation of its biosynthesis is a hierarchical, multifactorial process, which is highly integrated in the metabolism of A. fumigatus, and some studies point to the involvement of the G protein-coupled receptor (GPCR, GprK) and the pathways of MAP kinases, more specifically for the mitogen-activated protein kinase (MPKA) MpkA. Our research group has generated extremely relevant data in the areas of A. fumigatus biology, mainly in the understanding of MAP kinase-mediated cell signaling of the pathogen. In addition, recently, we identified 16 new transcription factors with possible involvement in gliotoxin biosynthesis, since the null mutants for these genes showed sensitivity to gliotoxin. In addition, some of them obtained altered production of gliotoxin and bisdethiobis(methylthio)GT , suggesting an important role of these FTs in the biosynthesis of GT and also in the mechanism of self-protection of GT in A. fumigatus. In this context, exploring a putative mechanism for regulating GT production via GprK-MpkA-FTs, checking a probable connection between GprK and MpkA, and verifying a possible involvement of MpkA in the expression of the identified FTs and their role in the GT biosynthesis and self-protection will be of great importance for a deeper understanding of the establishment of the virulence and infection program in A. fumigatus.

Scientific publications

(11)

(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)

DA COSTA FILHO, AILTON PEREIRA; PEREIRA BRANCINI, GUILHERME THOMAZ; DE CASTRO, PATRICIA ALVES; VALERO, CLARA; FERREIRA FILHO, JAIRE ALVES; SILVA, LILIAN PEREIRA; ROCHA, MARINA CAMPOS; MALAVAZI, IRAN; DE MORAES PONTES, JOAO GUILHERME; FILL, TAICIA; et al. Aspergillus fumigatus G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence. MBIO, v. 11, n. 5, SEP-OCT 2020. (16/07870-9, 18/10962-8, 18/25217-6, 19/11929-7, 17/14159-2, 16/12948-7, 18/00715-3, 19/10727-1, 19/06359-7, 16/21392-2)

DOS REIS, THAILA FERNANDA; CRIVELENTE HORTA, MARIA AUGUSTA; COLABARDINI, ANA CRISTINA; FERNANDES, CAROLINE MOTA; SILVA, LILIAN PEREIRA; BASTOS, RAFAEL WESLEY; DE LAZARI FONSECA, MARIA VITORIA; WANG, FANG; MARTINS, CELSO; RODRIGUES, MARCIO L.; et al. Screening of Chemical Libraries for New Antifungal Drugs against Aspergillus fumigatus Reveals Sphingolipids Are Involved in the Mechanism of Action of Miltefosine. MBIO, v. 12, n. 4, JUL-AUG 2021. (16/07870-9, 16/12948-7)

ANNICK RIES, LAURE NICOLAS; DE CASTRO, PATRICIA ALVES; SILVA, LILIAN PEREIRA; VALERO, CLARA; DOS REIS, THAILA FERNANDA; SABORANO, RAQUEL; DUARTE, IOLA F.; PERSINOTI, GABRIELA FELIX; STEENWYK, JACOB L.; ROKAS, ANTONIS; et al. spergillus fumigatus Acetate Utilization Impacts Virulence Traits and Pathogenicit. MBIO, v. 12, n. 4, JUL-AUG 2021. (16/07870-9, 17/14159-2, 17/08750-0, 16/12948-7, 18/00715-3)

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; et al. 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. (17/07536-4, 16/21392-2, 14/06863-3, 16/12948-7, 16/07870-9, 16/22062-6, 14/04783-2, 17/19288-5)

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; et al. Novel Biological Functions of the NsdC Transcription Factor in Aspergillus fumigatus. MBIO, v. 12, n. 1, JAN-FEB 2021. (16/07870-9, 18/00715-3, 16/21392-2, 17/07536-4, 16/22062-6, 16/12948-7, 19/10097-8)

VALERO, CLARA; COLABARDINI, ANA CRISTINA; CHIARATTO, JESSICA; PARDESHI, LAKHANSING; DE CASTRO, PATRICIA ALVES; FERREIRA FILHO, JAIRE ALVES; SILVA, LILIAN PEREIRA; ROCHA, MARINA CAMPOS; MALAVAZI, IRAN; COSTA, JONAS HENRIQUE; et al. Aspergillus fumigatus Transcription Factors Involved in the Caspofungin Paradoxical Effect. MBIO, v. 11, n. 3, p. 22-pg., 2020-05-01. (16/21392-2, 17/07536-4, 16/12948-7, 16/07870-9, 16/22062-6, 18/00715-3)

DE CASTRO, PATRICIA ALVES; COLABARDINI, ANA CRISTINA; MORAES, MAISA; HORTA, MARIA AUGUSTA CRIVELENTE; KNOWLES, SONJA L.; RAJA, HUZEFA A.; OBERLIES, NICHOLAS H.; KOYAMA, YASUJI; OGAWA, MASAHIRO; GOMI, KATSUYA; et al. Regulation of gliotoxin biosynthesis and protection in Aspergillus species. PLOS GENETICS, v. 18, n. 1, p. 34-pg., 2022-01-01. (18/10962-8, 16/07870-9, 17/14159-2, 16/12948-7)

VALERO, CLARA; COLABARDINI, ANA CRISTINA; DE CASTRO, PATRICIA ALVES; AMICH, JORGE; BROMLEY, MICHAEL J.; GOLDMAN, GUSTAVO H.. The Caspofungin Paradoxical Effect is a Tolerant "Eagle Effect" in the Filamentous Fungal Pathogen Aspergillus fumigatus. MBIO, v. N/A, p. 6-pg., 2022-04-14. (16/12948-7, 16/07870-9, 18/00715-3, 17/07536-4)

ANNICK RIES, LAURE NICOLAS; ROCHA, MARINA CAMPOS; DE CASTRO, PATRICIA ALVES; SILVA-ROCHA, RAFAEL; SILVA, ROBERTO NASCIMENTO; FREITAS, FERNANDA ZANOLLI; DE ASSIS, LEANDRO JOSE; BERTOLINI, MARIA CELIA; MALAVAZI, IRAN; GOLDMAN, GUSTAVO H.. The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect. MBIO, v. 8, n. 3, MAY-JUN 2017. (16/12948-7, 12/23942-9, 13/22375-6)

BASTOS, RAFAEL WESLEY; AKIYAMA, DANIEL; DOS REIS, THAILA FERNANDA; COLABARDINI, ANA CRISTINA; LUPERINI, RAFAEL SANCHEZ; DE CASTRO, PATRICIA ALVES; BALDINI, REGINA LUCIA; FILL, TAICIA; GOLDMAN, GUSTAVO H.. Secondary Metabolites Produced during Aspergillus fumigatus and Pseudomonas aeruginosa Biofilm Formation. MBIO, v. 13, n. 4, p. 17-pg., 2022-07-20. (17/07536-4, 21/07038-0, 21/11062-3, 17/19821-5, 16/07870-9, 21/00728-0, 16/12948-7)

VALERO, CLARA; COLABARDINI, ANA CRISTINA; DE CASTRO, PATRICIA ALVES; SILVA, LILIAN PEREIRA; RIES, LAURE NICOLAS ANNICK; PARDESHI, LAKHANSING; WANG, FANG; ROCHA, MARINA CAMPOS; MALAVAZI, IRAN; SILVA, ROBERTO NASCIMENTO; et al. Aspergillus Fumigatus ZnfA, a Novel Zinc Finger Transcription Factor Involved in Calcium Metabolism and Caspofungin Tolerance. FRONTIERS IN FUNGAL BIOLOGY, v. 2, p. 16-pg., 2021-08-10. (16/21392-2, 17/07536-4, 16/12948-7, 16/07870-9, 18/00315-5, 17/19694-3, 18/00715-3, 17/14159-2)