How bacteria defend themselves against their viruses ?
Facing the abundance and diversity of their viruses, bacteria and archaea have developed multiple lines of defense that can be referred to as “prokaryotic anti-viral systems“. Our research focuses on these anti-phage systems.
We are trying to understand evolutionary patterns and molecular mechanisms of these systems but also how to use them for medical applications. We work at several scales: from computational genomic analysis on thousands of prokaryotic genomes to experimental molecular genetics and diverse microbiology tools.
We are currently working on the ecology and evolution of anti-phage systems, their conservation with eukaryotic immune systems and how we can harness them for the fight against pathogens.
You can learn more about our field of research through the podcast Micrboes and Us by FEMS where we discussed anti viral defense in bacteria (Episode 12).
Systematically detecting anti-phage systems in genomes
In the past few years, the world of anti-viral mechanisms in bacteria got crazy with the discovery of many novel systems with crazy cool mechanisms. Their numbers exploded, and so we ended up a bit lost. How many of these bacteria have? Which one is encoded by my favorite bug ?
Bacteria and archaea have developed multiple antiviral mechanisms, and genomic evidence indicates that several of these antiviral systems co-occur in the same strain. Here, we introduce DefenseFinder, a tool that automatically detects known antiviral systems in prokaryotic genomes. We use DefenseFinder to analyse 21000 fully sequenced prokaryotic genomes, and find that antiviral strategies vary drastically between phyla, species and strains. Variations in composition of antiviral systems correlate with genome size, viral threat, and lifestyle traits. DefenseFinder will facilitate large-scale genomic analysis of antiviral defense systems and the study of host-virus interactions in prokaryotes.
Publication: Systematic and quantitative view of the anti-viral arsenal of prokaryotes
Tesson F., Hervé A., Touchon M., Mordret E., d’Humières C., Cury J., Bernheim A. Nature Communications, 13:256 (2022)
Twitter thread explaining the discovery
Scientific Commentary: Nature Reviews Microbiology
Previous relevant research
You can discover the post doctoral work of Aude through a seminar she gave in July 2020
Prokaryotic viperins, a novel family of defense systems that produce antiviral molecules
Viperin is an important anti-viral protein of humans that is conserved in animals. It has been shown to inhibit the replication of multiple human viruses by producing a molecule called ddhCTP, which acts as a chain terminator for viral RNA polymerase (Gizzi et al. 2018).
We showed that eukaryotic viperin originated from a clade of bacterial and archaeal proteins that protect against phage infection. Prokaryotic viperins produce a set of modified ribonucleotides that include ddhCTP, ddhGTP and ddhUTP. We further showed that prokaryotic viperins protect against T7 phage infection by inhibiting viral polymerase-dependent transcription, suggesting that it has an antiviral mechanism of action similar to that of animal viperin.
This study showed for the first time that natural antiviral compounds are produced by bacterial immune systems, opening avenues to look for more anti-viral molecules generated by bacteria. It’s also the first time such a strong conservation between a eukaryotic and prokaryotic immune system was demonstrated.
Publication: Prokaryotic viperins produce diverse antiviral molecules.
Bernheim A. Millman A., Ofir G., Meitav G., Abraham C., Shomar H., Rosenberg M., Tal N., Melamed S., Amitai G., Sorek R. Nature, (2021)
Twitter thread explaining the discovery
Scientific Commentary: Cell Host and Microbes
General public summary: English or French:
Press: Times of Israel, Jerusalem Post, News1, israel21, Sciences et avenir…
Retrons, mysterious bacterial elements function in anti-phage defense
With two collaborators (Adi Millman and Avigail Stokar-Avihail), we elucidated the physiological functions of genetic elements that had been a mystery for 30 years: retrons. Retrons are bacterial genetic elements comprised of a reverse transcriptase (RT) and a non-coding RNA (ncRNA). We stumbled upon a defense system that encodes a retron. This led us to hypothesize that all retrons function as defense systems. We found out that the defensive unit is composed of three components: the RT, the ncRNA, and an effector protein. We examined multiple retron systems and show that they confer defense against a broad range of phages via abortive infection. Focusing on retron Ec48, we showed evidence that it ‘‘guards’’ RecBCD, a complex with central anti-phage functions in bacteria. Inhibition of RecBCD by phage proteins activates the retron, leading to abortive infection and cell death. Thus, the Ec48 retron forms a second line of defense that is triggered if the first lines of defense have collapsed.
This study solved a three-decades old question, and demonstrated a novel concept in bacterial immunology (the guard hypothesis) inspired by the plant immunology field and conserved in prokaryotes.
Publication: Bacterial retrons function in anti- phage defense
Millman A*, Bernheim A*, Stokar-Avihail A.*, Fedorenko T., Voichek M., Leavitt A., Sorek R.
Our Twitter thread explaining the discovery
Scientific Commentaries: Science, The CRISPR journal, Nature Reviews Microbiology
General public summary:English
Press: Jerusalem Post, Phys.org, Drug and Target Review, Science Daily…
Diversity and ecology of defense systems
This perspective provides a conceptual framework for the evolutionary forces that lead to the diverse immune systems and their original distribution in bacterial genomes.
The recent discovery of the unexpected diversity of prokaryotic immune arsenal have led to seemingly contradictory observations: on one hand, individual microorganisms often encode multiple distinct defense systems, some of which are acquired by horizontal gene transfer, suggesting they yield a fitness benefit. On the other hand, defense systems are frequently lost from prokaryotic genomes on short evolutionary time scales, suggesting that they impose a fitness cost. We introduced the ‘pan-immune system’ model in which we suggest that, although a single strain cannot carry all possible defense systems owing to their burden on fitness, it can employ horizontal gene transfer to access immune defense mechanisms encoded by closely related strains. Thus, we propose that the ‘effective’ immune system is not the one encoded by the genome of a single microorganism but rather by its pan-genome, comprising the sum of all immune systems available for a microorganism to horizontally acquire and use.
The bacterial pan-immune system: anti-phage defense as a community resource
Bernheim A, Sorek R
Nature Reviews Microbiology 18, 113–119 (2020)