The role of lactose and acetate metabolism in Aspergillus fumigatus virulence

• Grant number: 17/14159-2
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: November 01, 2017
• End date: June 30, 2020
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Laure Nicolas Annick Ries
• Grantee: Laure Nicolas Annick Ries
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Roberto do Nascimento Silva
• Associated research grant(s): 19/16291-0 - Identification of Aspergillus fumigatus protein kinases and phosphatases important for the anti-fungal drug response, AP.R SPRINT
• Associated scholarship(s): 18/01475-6 - The role of lactose and acetate metabolism in Aspergillus fumigatus virulence, BP.JP

Abstract

Aspergillus fumigatus is a prominent opportunistic human fungal pathogen, that can cause a range of diseases, whose severity depends on the underlying disturbance in the host immune system. A. fumigatus possesses a range of virulence factors that determine its pathogenicity and allow successful colonisation of the host. Nutrient acquisition and subsequent metabolic processes are essential for initial colonisation and promoting fungal survival within the human host. The acquisition of essential minerals such as iron, zinc, and copper are essential for A. fumigatus pathogenicity, whereas little information exists on carbon source utilisation during infection, although they are required in large quantities to sustain biosynthetic processes. Furthermore, growth on a given carbon source has been shown to affect cell wall composition, another important virulence factor, therefore altering the solicited immune response and susceptibility to antifungal drugs. The main carbon sources encountered by A. fumigatus during infection are glucose, lactate and acetate, whose availability depends on the host niche and inflammation status. Whereas glucose metabolism and -related Carbon Catabolite Repression (CCR) have been studied in A. fumigatus, virtually nothing is known about lactate and acetate utilisation, although the genome encodes all components required for the uptake and subsequent metabolism of these carbon sources. This project therefore proposes to thoroughly investigate a role of lactate and acetate utilisation in A. fumigatus virulence. This work will start by identifying genes, via RNA sequencing, which are involved in lactate and acetate utilisation. Deletion strains will be generated for the identified genes and phenotypic characterisation, phagocytosis and virulence assays will be carried out for the same strains. In addition, metabolic flexibility analysis and metabolite analysis will be carried out to determine changes in metabolic pathways when grown in the presence of lactate and acetate and compared to glucose-grown cells. Furthermore, this project aims at determining differences in the composition of the cell wall in the presence of glucose, lactate and acetate and correlate this with increased susceptibility or resistance to antifungal agents and extracellular stresses. This project is expected to generate novel data which will further contribute to elucidating the A. fumigatus-mediated process of infection, therefore providing a relatively new and uncharacterised angle on A. fumigatus infection biology which could prove useful for laying a basis for a better comprehension of the disease and the possible development of novel and/or more efficient antifungal agents. (AU)

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)

STEENWYK, JACOB L.; LIND, ABIGAIL L.; RIES, LAURE N. A.; DOS REIS, THAILA F.; SILVA, LILIAN P.; ALMEIDA, FAUSTO; BASTOS, RAFAEL W.; FRAGA DA SILVA, THAIS FERNANDA DE CAMPOS; BONATO, VANIA L. D.; PESSONI, ANDRE MOREIRA; et al. Pathogenic Allodiploid Hybrids of Aspergillus Fungi. Current Biology, v. 30, n. 13, p. 2495+, JUL 6 2020. (17/14159-2, 16/03322-7, 16/07870-9)

DE ASSIS, LEANDRO JOSE; SILVA, LILIAN PEREIRA; BAYRAM, OZGUR; DOWLING, PAUL; KNIEMEYER, OLAF; KRUEGER, THOMAS; BRAKHAGE, AXEL A.; CHEN, YINGYING; DONG, LIGUO; TAN, KAELING; et al. Carbon Catabolite Repression in Filamentous Fungi Is Regulated by Phosphorylation of the Transcription Factor CreA. MBIO, v. 12, n. 1, JAN-FEB 2021. (16/03900-0, 16/07870-9, 14/00789-6, 17/14159-2)

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)

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)

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)

ANNICK RIES, LAURE NICOLAS; STEENWYK, JACOB L.; DE CASTRO, PATRICIA ALVES; ALMEIDA DE LIMA, POLLYNE BORBOREMA; ALMEIDA, FAUSTO; DE ASSIS, LEANDRO JOSE; MANFIOLLI, ADRIANA OLIVEIRA; TAKAHASHI-NAKAGUCHI, AZUSA; KUSUYA, YOKO; HAGIWARA, DAISUKE; et al. Nutritional Heterogeneity Among Aspergillus fumigatus Strains Has Consequences for Virulence in a Strain- and Host-Dependent Manner. FRONTIERS IN MICROBIOLOGY, v. 10, APR 24 2019. (16/03322-7, 17/14159-2)

JOHNS, LOUISE E.; GOLDMAN, GUSTAVO H.; RIES, LAURE N. A.; BROWN, NEIL A.. Nutrient sensing and acquisition in fungi: mechanisms promoting pathogenesis in plant and human hosts. FUNGAL BIOLOGY REVIEWS, v. 36, p. 1-14, JUN 2021. (17/14159-2, 16/07870-9, 18/22040-8)

BASTOS, RAFAEL WESLEY; VALERO, CLARA; SILVA, LILIAN PEREIRA; SCHOEN, TAYLOR; DROTT, MILTON; BRAUER, VERONICA; SILVA-ROCHA, RAFAEL; LIND, ABIGAIL; STEENWYK, JACOB L.; ROKAS, ANTONIS; et al. Functional Characterization of Clinical Isolates of the Opportunistic Fungal Pathogen Aspergillus nidulans. MSPHERE, v. 5, n. 2, MAR-APR 2020. (19/00631-7, 18/14762-3, 16/07870-9, 17/14159-2, 17/19821-5)

RIES, LAURE N. A.; PARDESHI, LAKHANSING; DONG, ZHICLIANG; TAN, KAELING; STEENWYK, JACOB L.; COLABARDINI, ANA CRISTINA; FERREIRA FILHO, JAIRE A.; DE CASTRO, PATRICIA A.; SILVA, LILIAN P.; PREITE, NYCOLAS W.; et al. The Aspergillus fumigatus transcription factor RglT is important for gliotoxin biosynthesis and self-protection, and virulence. PLOS PATHOGENS, v. 16, n. 7, JUL 2020. (17/14159-2, 17/21983-3, 18/25217-6, 17/07536-4, 17/01188-4, 13/50954-0, 14/00789-6, 13/07937-8, 16/07870-9, 19/09278-8, 16/03322-7)

DROTT, M. T.; BASTOS, R. W.; ROKAS, A.; RIES, L. N. A.; GABALDON, T.; GOLDMAN, G. H.; KELLER, N. P.; GRECO, C.. Diversity of Secondary Metabolism in Aspergillus nidulans Clinical Isolates. MSPHERE, v. 5, n. 2, MAR-APR 2020. (17/14159-2, 17/19821-5, 19/00631-7, 16/07870-9)

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)