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Study Suggests CRISPR Gives Evolutionary Edge to Phages Escaping Bacterial Defense

NEW YORK (GenomeWeb) – The CRISPR-Cas9 system may do more than protect against invading phages in its native bacterial environment, new research suggests. Findings from experiments in Escherichia coli suggest it can also speed up the evolution of some of these bacteria-infecting viruses.

Researchers from the US and China used bacterial plaque assays, DNA sequencing, and other approaches to track the consequences of the "clustered regularly interspaced short palindromic repeat" (CRISPR)-Cas activity in the E. coli. Their results, appearing online today in Science Advances, revealed incomplete cleavage of the T4 phage genome, along with enhanced mutation and evolution in the phages that managed to dodge this form of bacterial adaptive defense.

"The mutation frequencies are, remarkably, approximately six orders of magnitude higher than the spontaneous mutation frequency in the absence of CRISPR pressure," senior author Venigalla Rao, a biology researcher at the Catholic University of America, and his co-authors wrote. "Our findings lead to the hypothesis that that CRISPR-Cas might be a double-edged sword, providing survival advantages to both bacteria and phages, leading to their co-evolution and abundance on Earth."

Broadly speaking, the CRISPR-Cas system works by cutting the phage genome and plopping 20 to 40 base pair phage spacer sequences into CRISPR arrays in the bacterial genome, the team explained. These arrays encode CRISPR RNAs that stand on guard for and cleave similar phage sequences through precise sequence targeting that has been tweaked for gene editing applications.

"The bacterial genome is protected because the spacers in its CRISPR array lack additional recognition elements such as the [protospacer adjacent motif] sequence," the authors wrote. "The cleaved phage genome is cannibalized, potentially to acquire additional spacers, and is no longer able to support a productive phage infection."

In an effort to better characterize CRISPR-Cas biology in the context of bacterial host and phage virus interactions, the researchers searched for circumstances leading to T4 phage survival or demise in E. coli bacteria expressing a type II CRISPR-Cas9 system from Streptococcus pyogenes. In this model system, they evaluated mutant T4 phages that are known to be better at escaping CRISPR-Cas9 as well as a wild type version of the T4 phage.

After assaying for bacterial plaques with CRISPR escape mutant T4 phages, the team used sequencing to look at spacer sequences in the CRISPR-resistant phages, uncovering recurrent mutations in protospacer or protospacer adjacent motif sequences in phages with high-restriction spacers that successfully dodged the CRISPR-Cas9 system.

From these and other experiments, the researchers successfully tested a model whereby CRISPR-Cas9 escape prompts enhanced mutation frequency and faster-than-usual evolution in the phages that are prone to escaping the bacterial defense system.

"[O]ur results suggest the possibility that the defensive and counterdefensive systems of the arms race between bacteria and phages such as the CRISPR-Cas may have been selected for the survival advantages that they provide to both the host and the virus," the authors concluded, "but not merely to one or the other, such that both the bacteria and the phages can coexist and co-evolve, leading to their dominant presence on Earth."

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