Immunopathogenicity of clinical isolates of Aspergillus nidulans

• Grant number: 24/16021-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2025
• End date: December 31, 2026
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Gustavo Henrique Goldman
• Grantee: Peter Silva Rocha
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The pathogenic opportunistic fungus of the genus Aspergillus ssp is the main cause of more than two million infections worldwide. The colonization of fungal strains in the host depends on the regulation, synthesis and remodeling of proteins that organize themselves to constitute the integrity of the cell wall and thus adapt to cellular oxidative stress and ensure its survival. Invasive pulmonary aspergillosis (IA) is a disease caused by these microorganisms that mainly affects immunocompromised individuals or those with preexisting lung conditions. Aspergillus nidulans infections seem to demonstrate a preference for the host of chronic granulomatous disease (CGD), a disease understood as a primary and hereditary immunodeficiency of nicotinamide adenine nucleotide phosphate (NADPH) oxidase in which phagocytes fail to produce reactive oxygen species (ROS). Although there are reports in the literature of the pathogenicity of A. nidulans strains in the vertebrate host, it is still unclear which genomic and proteomic characteristics are related to the pathogenicity of clinical isolates of A. nidulans, since the information found in the literature does not cover the great diversity of strains present in the environment, which makes the available data inconclusive. To address this question and obtain more information about the pathology of A. nidulans, we propose to evaluate the immunopathogenicity of different clinical isolates of A. nidulans and understand about their virulence in cell and animal models and understand about their best establishment in patients with CGD. For this, we will perform a screening of 25 strains of A. nidulans from clinical isolates through killing experiments and cell viability of macrophages, in addition to the dosage of inflammatory mediators. After this characterization, we will infect immunocompetent (WT), immunosuppressed and CGD mice to evaluate the survival curve and resistance of these animals to infection. We will also perform the measurement of cytokines in the serum, lymphoid organs and lungs, in addition to the characterization of circulating leukocytes and mRNA expression in the lung tissue. We will perform genomic and proteomic analyses of these clinical isolates and evaluate the potential of antifungal and oxidative stress drugs. In the end, we hope to identify the pathogenic profile of A. nidulans strains and identify possible virulence factors that provide their establishment in the vertebrate host, in addition to their better establishment in patients with CGD.