Solving the riddles of cell death to cure long-term inflammation in cystic fibrosis

The human body is a complex system composed of quadrillion cells. Healthy cells live and die, and their lifetime is precisely regulated and controlled via so-called regulated cell death mechanisms. These highly specialised processes play a key role in maintaining stable conditions within the body, allowing it to eliminate cells that are no longer useful or may become dangerous. However, sometimes they are disrupted, and cells begin to divide in an uncontrolled way, leading to oncogenesis.

Developing a spatial model of a potential drug via computer simulations, photo by Studio AiR Bros, Toruń In 2012, the scientific community was moved by the proposed concept of a new mechanism of regulated cell death, characterised by the formation and accumulation of so-called lipid peroxides, which cause extensive membrane damage and dysfunction of other proteins. The process was called ferroptosis. It is normally used to eliminate useless or potentially dangerous cells but has also been identified as a cell death mechanism involved in Parkinson’s and Alzheimer’s disease and sepsis, as well as a factor contributing to tissue degradation in brain trauma, kidney disorders, and asthma. The initiation of ferroptosis could also find promising applications in the therapy of treatment-resistant cancers.

Interestingly, research implies that ferroptosis can be induced and used by P. aeruginosa in the pathology of pneumonia and cystic fibrosis. This bacterium is considered by the World Health Organization as a pathogen with high medical importance because its infecting abilities and multidrug resistance result in long-term chronic airway infections in patients with cystic fibrosis. These people suffer since currently, there are only possibilities to minimise the symptoms of infections, but there is no effective long-term prevention for their condition. The goal of the project is to address this problem and solve the riddles behind P. aeruginosa-induced ferroptosis in humans in order to improve the quality of life for people with cystic fibrosis and other disorders associated with this bacterium.

Dr hab. Karolina Mikulska-Rumińska, photo by Studio AiR Bros, Toruń The project uses computational methods such as molecular dynamics and molecular docking simulations, together with bioinformatics and programming abilities, to uncover the mechanisms that are used by P. aeruginosa to initiate ferroptosis in human cells and ultimately deliver new chemical compounds that could serve as a basis for potential drugs to treat pneumonia and cystic fibrosis. We are also planning to develop a new computational tool that will be available for other scientists as part of the program called ProDy (a Python package), in use since 2011. Our modelling results, including potential inhibitors, will be tested in biochemical experiments by our project collaborators.

Based on state-of-the-art biomolecular modelling methods, the project will bring us closer to an in-depth understanding of ferroptosis in the hope of developing new intervention methods for long-term infections in patients with cystic fibrosis and other P. aeruginosa-induced diseases.