Grant: Discovery Grants Program - Individual

Bacteria are social organisms that live in communities. Accordingly, sensing and interacting with the environment is of critical importance for bacteria, and a wide array of structures are displayed at the bacterial cell surface for these purposes. The outer membrane makes the translocation of molecules at the surface particularly challenging for Gram-negative bacteria, and to this end, they use different systems that range in complexity, from the simple T5SS (for Type 5 Secretion System) to complex, multi-subunit nanomachines like the T4SS or T6SS. These systems are involved in virulence and/or microbe-microbe interactions, and thus, deciphering the global requirements for their biogenesis and function is particularly important to understand how bacteria cause infections. Traditionally, these surface structures have been studied using a reductionist approach that simplifies the bacterial complexity in order to focus on the system itself. While this strategy has generated a great amount of information on their structure and function, how their assembly is integrated within the cell physiology remains mostly unknown. Thus, new approaches are required to fully understand the biogenesis and function of these multi-subunit complexes. The goal of this research proposal is to explore the biogenesis and function of complex surface structures. In particular, this proposal aims at developing new methodologies to study the biogenesis and the function of surface structures such as the T4SS, T5SS, and T6SS using genome-wide approaches. As a first step, we will interrogate the complete genome of the model bacterium Escherichia coli and the related pathogen Salmonella Typhimurium to identify all the genes involved in the biogenesis and function of these systems, and characterize novel genetic interactions that contribute to the assembly and function of these systems. We will also generate deletions at key steps in the biogenesis of these secretion systems to determine how the assembly of these complex structures integrates into bacterial physiology. Overall, this proposal contains several technical innovations that will offer new possibilities for systems biology as a tool to study bacterial physiology and virulence. Furthermore, the results obtained will give us a better understanding of how bacteria assemble large protein complexes and provide insights into the biogenesis and the function of different secretion systems. Finally, this proposal will lead to new ideas to study how bacteria interact with their environment.