Understanding the pan-immune system of bacteria

The perpetual arms race between bacteria and phage resulted in the evolution of efficient phage-resistance systems.

Such systems, including restriction enzymes and CRISPR-Cas, have a major influence on the evolution of both bacteria and phage, and have also proven invaluable as molecular tools. We recently showed that the bacterial immune system is much richer than originally thought.

We discovered the CBASS system (Cohen, Nature 2019), prokaryotic viperins (Bernheim, Nature 2020), and additional defense systems widespread in microbes (Doron, Science 2018).

These discoveries relied on the observation that defense systems are organized in defense islands - areas in bacterial genomes where multiple defense systems are clustered together.

Mining defense islands resulted in the discovery of new defense systems, but our preliminary results suggest that this is just the tip of the iceberg, and that dozens of new defense systems remained undiscovered in microbial defense islands.

In this project we will use new genomic approaches, together with analyses of massive genomic and metagenomic datasets, to systematically map the molecular capabilities encoded within the anti-phage “defensome”.

The project combines computational genomics, synthetic biology, and deep genetic and biochemical experiments to discover, validate, and study the properties of new defense systems, as well as mechanisms used by phages to mitigate defense.

Specific focus will be given to retrons, microbial elements that produce chimeric molecules where RNA and DNA are covalently attached.

We discovered that retrons function in anti-phage defense, and plan to decipher the mechanism by which the RNA/DNA hybrid provides defense. Based on the enormous impact that antiviral systems had on modern molecular biology (e.g.

RNAi, CRISPR-Cas), we envision that deciphering the mechanism of new systems could yield not only major discoveries on phage-bacteria interactions, but also new and exciting molecular tools.