The journal Cell published two papers by independent teams of authors from the University of California (USA)* and the University of Exeter (UK)**, exploring the mechanisms by which bacteriophages resist the bacterial defense system CRISPR-Cas. Both papers indicate that bacteriophages can cooperate to overcome bacterial resistance.

It is known that many bacteria, like other living organisms, have a defense system against infectious agents—a kind of immune system. It is based on special DNA regions called clustered regularity short palindromic repeats, or CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats). Between the identical repeats are distinct DNA sequences called spacers, many of which are copies of sections of the genomes of viruses that parasitize the bacteria, known as bacteriophages. This serves as a kind of "criminal database" for the bacterial cell. The RNA synthesized by these CRISPR sequences, along with specialized Cas proteins (CRISPR-associated sequences), binds to complementary phage nucleic acids if they are introduced into the bacteria, triggering the destruction of the foreign nucleic acid by the Cas proteins. This is how bacteria protect themselves from infections.

When a phage attacks a bacterium, a real race ensues: can the CRISPR-Cas system find and destroy the phage DNA before the phage engulfs the bacterial cell? To buy time, some bacteria, such as Pseudomonas aeruginosa , create CRISPR RNA-protein complexes just in case, in advance, i.e., before the phage invasion begins. Therefore, when phage DNA enters the bacterium, the latter instantly destroys it. On the other hand, when phages infect bacteria, they initiate the synthesis of proteins that neutralize CRISPR-Cas complexes (anti-CRISPR proteins). However, if CRISPR-Cas proteins are already lying in wait for the phage DNA, the phage cannot produce anti-CRISPR proteins quickly enough to avoid damaging its own DNA. This is where cooperation comes into play: it turns out that the first phage to infect a cell uses anti-CRISPR proteins to neutralize the bacterial defense system, thus ensuring unimpeded replication of the second-invading phage. This "teamwork" of phages was demonstrated in experiments on Pseudomonas aeruginosa .

Fig. Graphical summary of the article by Landsberger M. et al., 2018**

The authors of the study believe** that their discovery will help improve the results of phage therapy by adjusting the doses of phage preparations to create a higher density of phages at the site of infection, since the effective destruction of certain bacteria first requires the neutralization of their defense systems.

* Borges AL, Zhang JY, Rollins MCF, et al. Bacteriophage Cooperation Suppresses CRISPR-Cas3 and Cas9 Immunity // Cell, 2018, 174(4): 917-925.E10 . DOI:https://doi.org/10.1016/j.cell.2018.06.013

** Landsberger M, Gandon S, Meaden S, et al. Anti-CRISPR Phages Cooperate to Overcome CRISPR-Cas Immunity // Cell, 2018, 174(4):908-916.E12 . DOI:https://doi.org/10.1016/j.cell.2018.05.058