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Understanding the pan-immune system of bacteria

Project description

Multiple anti-phage defence systems in bacteria

The arms race between bacteria and phages resulted in the creation of efficient anti-phage systems, including restriction enzymes and CRISPR-Cas, which also presented invaluable molecular genetics tools. Recent discoveries of additional bacterial defence systems included the cyclic-oligonucleotide-based anti-phage signalling systems (CBASS) and prokaryotic viperins and were based on the observation that they are clustered into defence islands in bacterial genomes. The preliminary results suggest that many anti-phage systems remain undiscovered in microbial defence islands. The EU-funded DefenseAgainstPhage project aims to discover, validate and study the properties of new systems and the mechanisms used by phages to overcome the defence. Discovering the new systems could yield not only an understanding of the phages-bacteria interactions but also new and exciting molecular tools.

Objective

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.

Host institution

WEIZMANN INSTITUTE OF SCIENCE
Net EU contribution
€ 2 500 000,00
Address
HERZL STREET 234
7610001 Rehovot
Israel

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Activity type
Higher or Secondary Education Establishments
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Total cost
€ 2 500 000,00

Beneficiaries (1)