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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

Qualitative behavior of regulated CRISPR modules.Depending on the activation level of CRISPR activity in free cells (δ), the host to phage protospacer ratio (β), and the CRISPR specific spacer deletion to acquisition rate ratio (GC), regulated CRISPR cassettes can fall in one of the four regimes: no advantage (regime I), advantageous to hosts by offering immune resistance and abortive infections (regime II and IV), or causing host extinction (regime III). Because per-spacer immune rates have been experimentally measured to be high, we do not study its influence specifically here. When CRISPR activity is completely repressed in free cells (δ = 0), regime III vanishes, and regime IV expands into its place. Notice that a low β value corresponds to efficient SND during acquisition process.
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pcbi.1004603.g007: Qualitative behavior of regulated CRISPR modules.Depending on the activation level of CRISPR activity in free cells (δ), the host to phage protospacer ratio (β), and the CRISPR specific spacer deletion to acquisition rate ratio (GC), regulated CRISPR cassettes can fall in one of the four regimes: no advantage (regime I), advantageous to hosts by offering immune resistance and abortive infections (regime II and IV), or causing host extinction (regime III). Because per-spacer immune rates have been experimentally measured to be high, we do not study its influence specifically here. When CRISPR activity is completely repressed in free cells (δ = 0), regime III vanishes, and regime IV expands into its place. Notice that a low β value corresponds to efficient SND during acquisition process.

Mentions: In this work, we analyzed the influence of infection-induced activation of CRISPRs and their autoimmunity side effect on prokaryote-phage coevolutionary dynamics. Our model integrates the classical ingredients of the prokaryotic CRISPR immune system, along with aspects of regulation and autoimmunity. Our analysis suggests that CRISPRs exploit both restriction and abortive infection. Moreover, we identified a key constraint that determines the growth advantage associated with CRISPRs as a prokaryotic immune system. As summarized in Fig 7, our model reveals a characteristic four-regime pattern determined principally by three effective parameters: the activation level of CRISPRs in uninfected population, the host to phage protospacer ratio, and spacer deletion to acquisition rate ratio in CRISPRs. In the presence of SND, the host to phage protospacer ratio is close to zero, and CRISPRs operate exclusively by exploiting restriction, while in the absence of SND, they tend to principally exploit the abortive infection route.


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)

Qualitative behavior of regulated CRISPR modules.Depending on the activation level of CRISPR activity in free cells (δ), the host to phage protospacer ratio (β), and the CRISPR specific spacer deletion to acquisition rate ratio (GC), regulated CRISPR cassettes can fall in one of the four regimes: no advantage (regime I), advantageous to hosts by offering immune resistance and abortive infections (regime II and IV), or causing host extinction (regime III). Because per-spacer immune rates have been experimentally measured to be high, we do not study its influence specifically here. When CRISPR activity is completely repressed in free cells (δ = 0), regime III vanishes, and regime IV expands into its place. Notice that a low β value corresponds to efficient SND during acquisition process.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi.1004603.g007: Qualitative behavior of regulated CRISPR modules.Depending on the activation level of CRISPR activity in free cells (δ), the host to phage protospacer ratio (β), and the CRISPR specific spacer deletion to acquisition rate ratio (GC), regulated CRISPR cassettes can fall in one of the four regimes: no advantage (regime I), advantageous to hosts by offering immune resistance and abortive infections (regime II and IV), or causing host extinction (regime III). Because per-spacer immune rates have been experimentally measured to be high, we do not study its influence specifically here. When CRISPR activity is completely repressed in free cells (δ = 0), regime III vanishes, and regime IV expands into its place. Notice that a low β value corresponds to efficient SND during acquisition process.
Mentions: In this work, we analyzed the influence of infection-induced activation of CRISPRs and their autoimmunity side effect on prokaryote-phage coevolutionary dynamics. Our model integrates the classical ingredients of the prokaryotic CRISPR immune system, along with aspects of regulation and autoimmunity. Our analysis suggests that CRISPRs exploit both restriction and abortive infection. Moreover, we identified a key constraint that determines the growth advantage associated with CRISPRs as a prokaryotic immune system. As summarized in Fig 7, our model reveals a characteristic four-regime pattern determined principally by three effective parameters: the activation level of CRISPRs in uninfected population, the host to phage protospacer ratio, and spacer deletion to acquisition rate ratio in CRISPRs. In the presence of SND, the host to phage protospacer ratio is close to zero, and CRISPRs operate exclusively by exploiting restriction, while in the absence of SND, they tend to principally exploit the abortive infection route.

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