Study of the relationship between genes involved in the cell wall integrity maintenance and thermotolerance in the human pathogenic fungi Aspergillus fumigatus

• Grant number: 15/17541-0
• Support Opportunities: Regular Research Grants
• Start date: November 01, 2015
• End date: October 31, 2017
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Iran Malavazi
• Grantee: Iran Malavazi
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Associated researchers: Anderson Ferreira da Cunha ; Julio Cesar Borges ; Lisandra Marques Gava Borges

Abstract

Aspergillus fumigatus is a saprophytic fungus and also an aggressive opportunistic pathogen responsible for the vast majority of cases of invasive pulmonary aspergillosis, the life threatening form of infection caused by this fungus. The relative resistance of fungi to mammals is attributed to a combination of the immune system activity and endothermy. The higher temperature of the blood of mammals creates an impeditive environment for fungal infection. So, fungi well adapted to survive at high temperatures, such as A. fumigatus, have increased fitness while infecting the mammal host. Upon temperature upshift, all organisms have a massive universal cellular response leading to changes in the gene expression program that culminates in the synthesis of heat shock proteins. In the yeast transcription factor HSF1 coordinates the expression of several heat shock-related genes, including the molecular chaperone Hsp90. It has been observed in other fungal organisms that Hsp90 is capable of regulating the function and stability of important cellular signaling pathways components. Among these signaling cascades is the cell wall integrity (CWI pathway). CWI pathway is a key modulator that controls the organization, biosynthesis and/or remodeling of the fungal cell wall. The cell wall is a major structure that provides physical and structural protection for the cell and one of the cellular components responsible for the interaction with the host during infection. However, the cell wall and its regulation mechanisms have not been fully exploited as a target of new chemotherapeutic antifungal agents. Our laboratory previously identified a genetic interaction between the main CWI pathway (PkcA, MpkA and RlmA) and the molecular chaperone Hsp90. These data indicate a direct correlation between the function of the regulatory system elicited by HSF1-Hsp90 and the integrity of the cell wall in A. fumigatus. Therefore, with this study we expect to provide information about the connection between the CWI pathway and at least two important heat-shock related genes in A. fumigatus (i.e., hsfA(HSF1) and hsp90). To achieve this goal, the main objectives of this project are: (i) molecular characterization of the gene encoding the possible functional homologue of yeast HSF1 transcription factor in A. fumigatus, named here as hsfA; (ii) evaluation of the CWI pathway activity during heat shock in A. fumigatus; (iii and iv) expression of recombinant proteins PkcA(409-1106), MpkA, RlmA and Hsp90 in bacterial system aiming to evaluate the physical interaction of the molecular chaperone Hsp90 with these CWI pathway components in A. fumigatus. (AU)

Scientific publications

(8)

(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)

PIVA, ROGER H.; ROCHA, MARINA C.; PIVA, DIOGENES H.; IMASATO, HIDETAKE; MALAVAZI, IRAN; RODRIGUES-FILHO, UBIRAJARA P.. Acidic Dressing Based on Agarose/Cs2.5H0.5PW12O40 Nanocomposite for Infection Control in Wound Care. ACS APPLIED MATERIALS & INTERFACES, v. 10, n. 37, p. 30963-30972, SEP 19 2018. (15/17541-0, 16/16098-8, 18/00315-5, 17/19694-3)

ROCHA, MARINA CAMPOS; MINARI, KARINE; FABRI, JOAO HENRIQUE TADINI MARILHANO; KERKAERT, JOSHUA D.; GAVA, LISANDRA MARQUES; DA CUNHA, ANDERSON FERREIRA; CRAMER, ROBERT A.; BORGES, JULIO CESAR; MALAVAZI, IRAN. Aspergillus fumigatusHsp90 interacts with the main components of the cell wall integrity pathway and cooperates in heat shock and cell wall stress adaptation. Cellular Microbiology, v. 23, n. 2, FEB 2021. (16/07870-9, 14/07206-6, 17/19694-3, 15/17541-0, 17/26131-5, 17/07335-9)

ROCHA, MARINA CAMPOS; TADINI MARILHANO FABRI, JOAO HENRIQUE; SIMOES, ISABELLE TAIRA; SILVA-ROCHA, RAFAEL; HAGIWARA, DAISUKE; DA CUNHA, ANDERSON FERREIRA; GOLDMAN, GUSTAVO HENRIQUE; CANOVAS, DAVID; MALAVAZI, IRAN. The Cell Wall Integrity Pathway Contributes to the Early Stages of Aspergillus fumigatus Asexual Development. Applied and Environmental Microbiology, v. 86, n. 7, APR 2020. (16/07870-9, 15/17541-0, 17/19694-3)

ROCHA, MARINA CAMPOS; DE GODOY, KRISSIA FRANCO; BANNITZ-FERNANDES, RENATA; MARILHANO FABRI, JOAO H. T.; FERRARI BARBOSA, MAYRA M.; DE CASTRO, PATRICIA ALVES; ALMEIDA, FAUSTO; GOLDMAN, GUSTAVO HENRIQUE; DA CUNHA, ANDERSON FERREIRA; NETTO, LUIS E. S.; et al. Analyses of the three 1-Cys Peroxiredoxins from Aspergillus fumigatus reveal that cytosolic Prx1 is central to H2O2 metabolism and virulence. SCIENTIFIC REPORTS, v. 8, AUG 17 2018. (14/16636-4, 16/03322-7, 15/17541-0, 13/22375-6)

ROCHA, MARINA CAMPOS; TADINI MARILHANO FABRI, JOAO HENRIQUE; SILVA, LILIAN PEREIRA; FIGUEIREDO ANGOLINI, CELIO FERNANDO; BERTOLINI, MARIA CELIA; DA CUNHA, ANDERSON FERREIRA; VALIANTE, VITO; GOLDMAN, GUSTAVO HENRIQUE; FILL, TAICIA PACHECO; MALAVAZI, IRAN. Transcriptional Control of the Production of Aspergillus fumigatus Conidia-Borne Secondary Metabolite Fumiquinazoline C Important for Phagocytosis Protection. Genetics, v. 218, n. 1, MAY 2021. (16/07870-9, 17/19694-3, 15/17541-0)

FABRI, JOAO HENRIQUE T. M.; ROCHA, MARINA C.; MALAVAZI, IRAN. Overview of the Interplay Between Cell Wall Integrity Signaling Pathways and Membrane Lipid Biosynthesis in Fungi: Perspectives for Aspergillus fumigatus. CURRENT PROTEIN & PEPTIDE SCIENCE, v. 21, n. 3, p. 265-283, 2020. (15/17541-0, 16/07870-9, 17/19694-3)

TADINI MARILHANO FABRI, JOAO HENRIQUE; GODOY, NAIANE LIMA; ROCHA, MARINA CAMPOS; MUNSHI, MANSA; COCIO, TIAGO ALEXANDRE; VON ZESKA KRESS, MARCIA REGINA; FILL, TAICIA PACHECO; DA CUNHA, ANDERSON FERREIRA; DEL POETA, MAURIZIO; MALAVAZI, IRAN. The AGC Kinase YpkA Regulates Sphingolipids Biosynthesis and Physically Interacts With SakA MAP Kinase in Aspergillus fumigatus. FRONTIERS IN MICROBIOLOGY, v. 9, JAN 14 2019. (15/17541-0, 17/19694-3)

PIVA, ROGER HONORATO; ROCHA, MARINA CAMPOS; PIVA, DIOGENES HONORATO; KLEGUES MONTEDO, OSCAR RUBEM; IMASATO, HIDETAKE; MALAVAZI, IRAN; RODRIGUES-FILHO, UBIRAJARA PEREIRA. Combating pathogens with Cs2.5H0.5PW12O40 nanoparticles: a new proton-regulated antimicrobial agent. JOURNAL OF MATERIALS CHEMISTRY B, v. 6, n. 1, p. 143-152, JAN 7 2018. (15/17541-0, 16/16098-8)