Viruses swipe bacterial immune system, turn it against hosts

The CRISPR narrative (pronounced "crisper") recently took a twist, with a team of Boston area scientists reporting that a virus has a CRISPR system of its own-to inactivate a separate host viral defense system.

Normally, CRISPR acts as a rudimentary immune system for bacteria against the onslaught of bacteria-targeting viruses, called phages. Bacteria that defend themselves with CRISPR have a series of short "spacer" sequences in their genome, flanked by repeats of the CRISPR sequence. These spacers contain pieces of the genomes of past invaders in the bacterial species's history. The bacterium transcribes these sequences into RNA, which are processed into smaller crRNAs, with each molecule targeting the sequence from a unique type of invader. If infiltrated by one such invader, the bacterium's crRNA targets the phage's genome for degradation.

It must have come as a surprise when Seed et al. (2013) found CRISPR sequences not in a bacterial genome, but in phage genomes. It turns out that the interplay between phages and the bacterium that causes cholera, Vibrio cholerae, plays a role in the severity of the infection in humans. When V. cholerae is hit with persistent attacks by phages, it is a less effective human pathogen. The researchers discovered that one of the tools up phages' sleeves is using CRISPR to inactive a V. cholerae anti-phage defense system. The host defense is unrelated to CRISPR, an innate immunity defense rather than CRISPR's adaptive defense (adaptive since DNA from new pathogens is stored in the bacterium's genome as additional spacers, giving protection against future infections).

By disabling the host's defense or phage's CRISPR system in various combinations, the authors demonstrated that CRISPR targeting of the host defense system is required for successful infection. This is the first time such an interaction has been described.

The implications are far-reaching, in both practical terms and basic science. For one, we face a startling antibiotics problem as mainstay treatments lose their effectiveness. Phage treatments might allow for targeted killing of the offending pathogens, while sparing the "good bacteria" that keep us healthy. Understanding phage-bacterium interactions in disease-relevant microbes like V. cholerae will be necessary for developing these sorts of treatments. A phage designer might, for instance, mistake the viral CRISPR system as junk cargo picked up through horizontal gene transfer. But we now know that, at least in this circumstance, the CRISPR system is necessary for the phage to infect its host. It also gives us another tool to fight back against bacteria, since we have a good understanding of how to engineer CRISPR.

From a basic science standpoint, it is becoming very clear that the sorts of evolutionary arms races long seen in the animal kingdom (the gazelle breeds speed in the lion, as lions breed swiftness in the gazelle) are also fought at the cellular and molecular level. Phages attack bacteria, which have defense systems against the phages, which the phages can subvert through their own mechanisms. Crucially, these arms races are surely spurred on by the rapid horizontal gene transfer that occurs between bacteria and phages. Bits of bacterial genome can end up in phage genomes, which can then be transferred to new bacteria. In this case, CRISPR was taken up by invading phages and turned against its rightful owners, the bacteria themselves-a case of turning the gun on its owner.

Interestingly, the GC content of the CRISPR region matched the overall GC content of the phage genome. GC content simply refers to the percentage of a gene or genome that is a G or a C, rather than an A or a T. If the GC content of a gene differs wildly from its neighbors or the genome overall, usually that is a good indication that the gene was recently acquired through horizontal gene transfer. Because the GC content of the viral CRISPR was the same as the rest of the genome, it appears the phages that infect V. cholerae acquired this trick long ago. Perhaps similar transfers have occurred in other groups of phages, yet to be discovered.

Image credits: V. cholerae: CDC/Dr. Edwin P. Ewing, Jr. (via Wikimedia); Phages (not the kind from the paper): Graham Beards (via Wikimedia)

Reference:

Seed, K. D. et al. A Bacteriophage Encodes its Own CRISPR/Cas Adaptive Response to Evade Host Innate Immunity. Nature 494, 489-491.