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

Kumar MS, Plotkin JB, Hannenhalli S - PLoS Comput. Biol. (2015)

Bottom Line: 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.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.More generally, we exploit numerical simulations to delineate four regimes of CRISPR dynamics in terms of its host, kinetic, and regulatory parameters.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Bioinformatics, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Elimination of ABI allows for improved phage densities.Steady state densities of free cells (A) and phages (B) for various values of free-cell CRISPR activity, δ. Both coexistence and phage densities are improved without ABI. Above a critical value of δ, the system goes to extinction.
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pcbi.1004603.g006: Elimination of ABI allows for improved phage densities.Steady state densities of free cells (A) and phages (B) for various values of free-cell CRISPR activity, δ. Both coexistence and phage densities are improved without ABI. Above a critical value of δ, the system goes to extinction.

Mentions: To study how ABI influences the coevolutionary dynamics in the general model, we remove the autoimmunity term from the model and compare the resulting prokaryotic and phage densities across several host protospacer and CRISPR activation levels (Fig 6). We find that while removing ABI in infected cells increases the size of the coexistence regime and allows for improved phage densities. Indeed, this is the same effect predicted by our bifurcation analysis of the simplified model, where lower abortive infection rates lead to increased coexistence owing to higher phage turnover.


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

Kumar MS, Plotkin JB, Hannenhalli S - PLoS Comput. Biol. (2015)

Elimination of ABI allows for improved phage densities.Steady state densities of free cells (A) and phages (B) for various values of free-cell CRISPR activity, δ. Both coexistence and phage densities are improved without ABI. Above a critical value of δ, the system goes to extinction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4636164&req=5

pcbi.1004603.g006: Elimination of ABI allows for improved phage densities.Steady state densities of free cells (A) and phages (B) for various values of free-cell CRISPR activity, δ. Both coexistence and phage densities are improved without ABI. Above a critical value of δ, the system goes to extinction.
Mentions: To study how ABI influences the coevolutionary dynamics in the general model, we remove the autoimmunity term from the model and compare the resulting prokaryotic and phage densities across several host protospacer and CRISPR activation levels (Fig 6). We find that while removing ABI in infected cells increases the size of the coexistence regime and allows for improved phage densities. Indeed, this is the same effect predicted by our bifurcation analysis of the simplified model, where lower abortive infection rates lead to increased coexistence owing to higher phage turnover.

Bottom Line: 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.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.More generally, we exploit numerical simulations to delineate four regimes of CRISPR dynamics in terms of its host, kinetic, and regulatory parameters.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Bioinformatics, University of Maryland, College Park, Maryland, United States of America.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus