Influence of Copper Exposure on the Induction of Dormancy and Non-Replicative State in bacteria of the Mycobacterium tuberculosis complex

• Grant number: 24/05174-1
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2024
• End date: March 31, 2026
• Field of knowledge: Biological Sciences - Microbiology - Biology and Physiology of Microorganisms
• Principal Investigator: Ana Marcia de Sá Guimarães
• Grantee: Ágatha Morgana Bertoti da Silva
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Tuberculosis (TB) is a disease with a wide global prevalence, with approximately 10.6 million new cases and 1.13 million deaths in 2022. The disease is caused by bacteria from the Mycobacterium tuberculosis complex (MTBC), presenting variations among strains adapted to humans and animals. Among those adapted to humans, Mycobacterium tuberculosis (Mtb) is the main agent of human TB, while Mycobacterium africanum (Maf) accounts for up to one-third of cases in West Africa. Other types, such as M. bovis (Mbo), are recognized as causes of animal and zoonotic TB and have a broader preference for host species. The survival of bacteria in macrophages, which are the main targets of these microorganisms, occurs through a variety of molecular mechanisms that allow evasion of the immune response. This includes transitioning to a dormant state and metabolic adaptations in response to stressors such as nitric oxide, carbon monoxide, and prolonged hypoxia, as well as harmful effects resulting from excess certain metals, such as copper. These elements directly influence the intracellular dynamics of Mtb. Therefore, the aim of this project is to analyze whether exposure to excess copper triggers a dormant and/or non-replicative state in Mtb, Maf, and Mbo. The study will employ in vitro dormancy models and methods for detecting non-replicative states and associated genotypic and phenotypic changes, such as analyses of dormancy-target gene expression, lipid inclusions, cell wall thickness, and assessments of non-replicative states with reporter plasmid by flow cytometry. It is expected to identify influences on gene regulation and phenotypic changes in the process of entry and exit from dormancy of MTBC bacteria regulated by copper, providing a better understanding of the survival mechanisms to stressors of these pathogens.