Exploring the Prokaryotic-Eukaryotic Conservation of Antiviral immunity: from bacterial immune systems to novel antiviral drugs

Project Information

PECAN

Grant agreement ID: 101040529

DOI

10.3030/101040529

EC signature date 22 April 2022

Start date 1 October 2022

End date 30 September 2027

Funded under

• European Research Council (ERC)

Total cost

€ 1 496 500,00

EU contribution

€ 1 496 500,00

Coordinated by

INSTITUT PASTEUR
France

Periodic Reporting for period 1 - PECAN (Exploring the Prokaryotic-Eukaryotic Conservation of Antiviral immunity: from bacterial immune systems to novel antiviral drugs)

Reporting period: 2022-10-01 to 2025-03-31

Summary of the context and overall objectives of the project

Bacteria have evolved multiple lines of defense against their viruses, bacteriophages. Such weapons include restriction modification and CRISPR systems that have greatly impacted biomedical research. Studies aimed at uncovering novel defense mechanisms describe an unsuspected diversity of anti-phage systems, spanning thousands of protein families. Several of these anti-phage systems, such as prokaryotic viperins, appear to be ancestors of major eukaryotic antiviral pathways. This striking conservation between eukaryotic and prokaryotic immunity leads me to three hypotheses on which the present proposal is based.
First, I postulate that the organisation of antiviral immunity in eukaryotes as an immune system, i.e. an integrated network of various antiviral mechanisms, might be conserved in prokaryotes. This implies that each anti-phage system does not act in isolation, but is rather part of a whole, the bacterial immune system. To explore this hypothesis, I will characterise the distribution of known anti-phage systems encoded in prokaryotic genomes. I will subsequently explore the potential synergies and co-regulation existing between these systems. I thereby aim to build an integrated map of bacteria antiviral immunity.
Second, I hypothesise that prokaryotes produce additional small anti-phage compounds, such as the viperin products, with a potential activity against eukaryotic viruses. To explore this idea, I will study the molecular mechanisms of the viperin family. I will then use genomics to predict novel chemical based anti-phage systems and follow up with their experimental characterizations. These projects could lead to the identification of novel antiviral molecules that could be further harnessed in the clinic.Finally I hypothesize that components of some of these recently-discovered antiphage
systems may be conserved in eukaryotes, and could potentially be identified through protein homology search. I envision that this approach of comparative immunology across domains of life can be leveraged to discover immune genes in eukaryotes.
Overall, I expect this proposal to generate new knowledge that will have the potential to radically change our view on the immune systems of prokaryotes and provide new therapeutic leads.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project undertook extensive scientific and technical activities, yielding groundbreaking insights into bacterial and eukaryotic immune systems. Through innovative computational and experimental approaches, we developed tools like DefenseFinder, now a gold standard in identifying bacterial antiviral systems, enabling the classification and exploration of defense mechanisms. Our research demonstrated that bacterial genomes encode a rich arsenal of defense systems, and our predictive algorithms uncovered surprising patterns in phage-bacteria interactions. We also identified novel biosynthetic gene clusters, leading to the discovery of lanthipeptides as potent antiviral agents, and established Streptomyces as a model organism for exploring chemical defenses.

The project expanded into evolutionary immunology, revealing how bacterial antiviral systems have been conserved and adapted in eukaryotes, including humans. We identified conserved immune genes, such as those linked to the TLR pathway, offering proof of concept for evolutionary ties between bacterial and human immunity. Studies on viperins highlighted the remarkable evolutionary trajectory of this protein family across all domains of life, while structural and functional studies provided new perspectives on immune system evolution.

Key outcomes include not only the discovery of novel antiviral agents and conserved immune mechanisms but also practical applications like tailored phage therapy strategies and potential immunotherapies. These achievements represent a significant leap in our understanding of the interplay between bacterial and eukaryotic immunity, with implications for both fundamental biology and therapeutic innovation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The project’s key results include a comprehensive framework for classifying bacterial defense systems, predictive algorithms for phage-bacteria interactions, and evolutionary insights into shared immunity across domains of life. The discovery of conserved immune genes and their roles in human immunity underscores the deep evolutionary ties between bacterial and eukaryotic systems, providing a roadmap for therapeutic development. These findings represent a significant leap forward, combining basic research with translational potential to address global health challenges.

To ensure further uptake and success, additional research is needed to refine computational tools for predicting defense systems and validate the functional roles of newly identified immune components in diverse organisms. Additional work could accelerate the translation of these findings into therapeutic applications. For example, much more research need to be done in the goal of translating discovery of antiviral peptides and tailored phage therapy solutions in the clinic