Regulated CRISPR Modules Exploit a Dual Defense Strategy of Restriction and Abortive Infection in a Model of Prokaryote-Phage Coevolution

CRISPRs offer adaptive immunity in prokaryotes by acquiring genomic fragments from infecting phage and subsequently exploiting them for phage restriction via an RNAi-like mechanism. Here, we develop and analyze a dynamical model of CRISPR-mediated prokaryote-phage coevolution that incorporates classical CRISPR kinetics along with the recently discovered infection-induced activation and autoimmunity side effects. Our analyses reveal two striking characteristics of the CRISPR defense strategy: that both restriction and abortive infections operate during coevolution with phages, driving phages to much lower densities than possible with restriction alone, and that CRISPR maintenance is determined by a key dimensionless combination of parameters, which upper bounds the activation level of CRISPRs in uninfected populations. We contrast these qualitative observations with experimental data on CRISPR kinetics, which offer insight into the spacer deletion mechanism and the observed low CRISPR prevalence in clinical isolates. More generally, we exploit numerical simulations to delineate four regimes of CRISPR dynamics in terms of its host, kinetic, and regulatory parameters.Author Summary: To counteract viral infections, bacteria and archaea have evolved a variety of defense systems. These can broadly be classified into either restriction or suicide mechanisms. The former enforces nicks in the invading DNA making it unusable for production of further infectious particles; the latter, by contrast, induces cell death whereby an infected cell activates specific host suicidal pathways that are otherwise strongly repressed, thus inhibiting further infection. Examples of the former class include restriction-modification (R-M) and the recently discovered CRISPR systems, while the latter class includes a variety of toxin/anti-toxin systems. CRISPRs, in contrast to R-Ms, adapt to target viral genomes by updating the database of target sites they recognize. The adverse side effect of such a mechanism, however, is that CRISPRs can target the host genome itself resulting in undesirable cell death (autoimmunity). The recent discovery of infection-induced activation of CRISPR systems suggests that these negative side effects may be limited to periods of infection. This led us to hypothesize that such regulatory control—similar to abortive infection mechanisms—can be advantageous by limiting viral spread through suicide of infected cells. To test this hypothesis, we mathematically model CRISPR induced prokaryote-phage coevolutionary dynamics in the presence of infection-regulated CRISPR activity. Our results indicate that, except in limited growth rates, regulated CRISPRs exploit both autoimmunity and target restriction and can therefore be considered a hybrid class that leverages both restriction and suicide mechanisms to limit phage infection.