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.
