anti-CRISPR · Selection and evolution of phage-encoded anti-CRISPR genes

Selection and evolution of phage-encoded anti-CRISPR genes

The bacterial adaptive immune systems CRISPR-Cas are of pivotal importance in nature where they protect bacteria against their viral predators (phages). In response, some phages evolved a sophisticated strategy by encoding anti-CRISPR proteins (Acrs). While our molecular understanding of Acr mechanisms has raced ahead, a fundamental question remains unexplored: what is the impact of acr genes on the ecological and evolutionary dynamics of phages and their hosts? This research project explored the costs and benefits associated with Acrs, their consequences on the composition and evolution of phage populations as well as on the evolution of their host. The main results of this project are important for society as they can be implemented in biomedical research, for the development of phage therapy to combat antibiotic-resistant bacteria, as well as in biotechnologies for a better control of Cas9-based genome editing. The research objectives of this project were the following: 1) Determine when Acrs are beneficial. Despite their potential benefits for phage survival, acr genes are absent from many phage genomes and they have been more frequently found in temperate phages (i.e. phages that have the ability to lying dormant into host genome), which suggests that their benefits may be dependent on phage genetic background. 2) Examine how Acrs impact the dynamics of phage communities. Our previous work showed that Acr-phages need to cooperate to bypass CRISPR-based resistance: a first Acr-phage enters the cell and shuts-off the CRISPR immune system, although this process is not rapid enough to go through the infection process successfully. This “sacrifice” allows a second Acr-phage to take over the immunosuppressed cell, produce progeny and kill the host. However, in nature, phage populations are often not clonal and composed of mixed genotypes, with some that encode Acrs and some that do not. Since Acr-phages generate hosts with weakened immunity, we speculate they may enable other phages to infect bacteria with CRISPR-Cas defences. 3) Explore how Acrs impact the evolution of bacteria. Because they block some of the Cas proteins that mediate immunity acquisition, Acrs may affect the emergence of CRISPR-based resistance and this may have consequences on the evolutionary dynamics of bacteria. These research questions were studied with a multidisciplinary approach that combined phage molecular biology, experimental evolution and mathematical modelling in the group of Prof. Westra (University of Exeter, UK).

Data: CORDIS, © European Union