Investigating secondary metabolites regulated by Sirtuin E (SirE) in Aspergillus fumigatus

• Grant number: 23/01824-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Effective date (Start): May 01, 2023
• Effective date (End): April 30, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: André Ricardo de Lima Damasio
• Grantee: Natália Sayuri Wassano
• Supervisor: Nancy P. Keller
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Research place: University of Wisconsin-Madison (UW-Madison), United States
• Associated to the scholarship: 20/01601-1 - The role of NAD+-dependent lysine deacetylases (sirtuin) and their inhibitors in Aspergillus fumigatus acetylome and virulence, BP.DD

Abstract

A. fumigatus is an opportunistic pathogenic fungus that infects immunosuppressed patients. It has a high mortality rate due in part to difficulties in diagnosing fungal infections and the emergence of antifungal-resistant strains. Understanding the biology of this fungus by applying genetic engineering and bioinformatics is fundamental to comprehending the function of new genes and finding potential drug targets. One promising strategy for treating fungal infections is targeting the enzymes that regulate protein acetylation. Sirtuins, an NAD+-dependent lysine deacetylase, have been described as histone deacetylase and as regulators of secondary metabolism in various Aspergillus spp, including in A. fumigatus (manuscript in preparation). Recently, the data obtained demonstrated that sirtuins are involved in growth, cell wall integrity, protease production, and virulence in A. fumigatus by changing the expression of several genes and the acetylation status of different proteins (histones and non-histones). Specifically, the hyperacetylation of histones and other proteins by sirtuins is involved in the production of known secondary metabolites (SMs), which are essential for A. fumigatus virulence (e.g gliotoxin) as determined by examining sirtuin deletion strains. In addition, a putative compound induced by the sirE deletion was annotated in ”AfSirE and SIRTko (six sirtuins deleted) strains. These strains also showed reduced virulence compared to parental strain in Galleria mellonella and murine infection models. We are proposing this research project in collaboration with Prof. Dr. Nancy Keller i) to validate and evaluate the potential of ”AfSirE strain for the biosynthesis of possible new SM by measuring the production in different culture conditions, ii) to solve the structure of these molecules iii) correlate transcriptome data of the ”AfSirE strain with SMs profile using database and bioinformatic tools developed by Keller's group and collaborators. (AU)