Bravo Group

Bacterial immune systems

Bacteria and parasitic mobile genetic elements (including phage and plasmids) are in an ongoing arms race. This tremendous evolutionary pressure has driven the development of a myriad of sophisticated bacterial defense systems capable of providing immunity. While well-known systems such as CRISPR-Cas have been extensively studied, the rise of metagenome analysis has unveiled a plethora of enigmatic defense mechanisms with unknown mechanisms. These systems must distinguish self from non-self molecules, requiring exquisite specificity to avoid unintended activation and autoimmunity.

The Bravo group is particularly interested in understanding how diverse bacterial immune systems can identify self from non-self nucleic acids, and the consequences of activation. We use a combination of structural biology (typically cryo-electron microscopy), biochemistry, biophysics and functional assays to understand the molecular mechanisms that underpin immunity. Our emphasis on cryo-electron microscopy and pre-steady state kinetic analysis enables the visualization of transient intermediate conformational states, providing insights into the active enzymes’ dynamic and heterogeneous nature.

Our ultimate goal is not only understanding these systems but harnessing that knowledge for rational structure-based engineering. Through this approach, we aim to redesign these defense systems, tailoring them to possess specific, desirable properties. These engineered systems typically exhibit enhanced efficiency and specificity, transforming into potent tools for genome editing and diagnostics. By tapping into the diverse enzymatic activities of newly discovered defense systems, we aspire to unveil a new arsenal of precision tools for molecular biology, poised to shape the future of biotechnological advancements.