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CRISPR vs. Anti-CRISPR: How bacterial viruses fight CRISPR-Cas immunity

Abstract

Bacteria and the viruses that infect them (bacteriophages/phages) are locked in an ancient evolutionary arms race. Bacteria use CRISPR-Cas systems as a form of anti-phage immunity and phages encode “anti-CRISPR” proteins that antagonize CRISPR-Cas function. Anti-CRISPRs are high-affinity CRISPR-Cas inhibitors, but face a great challenge in rapidly neutralizing all the CRISPR-Cas complexes in the cell upon phage infection. I show that CRISPR defeats phages with anti-CRISPRs in >90% of infection events, and rare successes occur only when multiple phages cooperate to infect the same cell. Failed infections “immunosuppress” the bacterium by the production of anti-CRISPRs prior to phage destruction, increasing chances of survival for other co-infecting phages. This is the first description of altruism in viruses. This cooperative strategy for CRISPR-Cas neutralization is completely dependent on phage multiplicity of infection: if the concentration of phage is too low for coinfections to occur at an appreciable rate, the phage population will go extinct. While this strategy may be suitable for some classes of mobile elements, others may be unable to obtain cooperation thresholds, necessitating enzymatic or hyper-potent inhibitors. In searching for new mechanisms of CRISPR-Cas neutralization, we have now discovered anti-CRISPRs that function substoichiometrically, one of which has been shown to be a multi-turnover enzyme. Furthermore, I show that some phages have hijacked a transcriptional repressor of CRISPR-Cas immunity, and deploy it to limit CRIPSR-Cas biogenesis. The CRISPR/anti-CRIPSR arms race is a hotbed for evolutionary innovation, and is a continuous source of novel and inventive mechanisms of immune neutralization.

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