Grant: Project Grant

Biofilms are slime-covered communities of microbes that stick to each other and to surfaces. This prevalent form of microbial life accounts for many chronic infections that defeat the immune system and are highly resistant to antibiotics. My work seeks to understand a process called signal transduction. All living cells use this process to sense external stimuli and trigger a chain of chemical events inside the cell, resulting in physiological adaptation to the environment. This project centers on signal transduction that coordinates biofilm growth. In many bacteria, biofilm signal transduction depends on a key intracellular molecule, cyclic diguanylate (c-di-GMP). I study c-di-GMP in the human pathogen Pseudomonas aeruginosa. This organism infects medical devices, the urinary tract and burn wounds. It also forms biofilms in the lungs of people suffering from cystic fibrosis (CF), causing life-threatening infections that can last for years. Nearly 4,000 Canadians suffer from CF. While a lot is known about how enzymes "make and break" c-di-GMP, little is known about the environmental stimuli that activate and inhibit these enzymes. This is a key research area because bacteria must use c-di-GMP signaling to sense and respond to host stimuli to build biofilms. C-di-GMP is a promising therapeutic target because it is absent in mammals. My lab has discovered that some isolates of P. aeruginosa have a protein that makes c-di-GMP in response to body heat. My 5-year project aims to understand - at a molecular and biophysical level - how this protein functions as a thermosensor and modulates virulence. Bioinformatics predict that this thermosensing protein is widespread among pathogens. My vision is that this research will guide the design of inhibitors targeting heat-sensing proteins that bacteria use to cause infection. Finally, I propose that these heat-sensing proteins can be reverse-engineered, enabling the design of thermally-activated proteins for biotechnology.