VALENCIA, 12 Jan. (EUROPA PRESS) –

An international research team led by the Institute of Biomedicine of Valencia (IBV), of the Higher Council for Scientific Research (CSIC), has discovered that certain phages, bacteria viruses, decide their infection strategy and their life cycle for a communication system “much more sophisticated and complex than previously believed.”

In a work published earlier this year in the journal ‘Nature Microbiology’, the research team reveals that this communication system involves a complex network of antagonistic interactions between proteins from the phage and the host bacteria. The finding deepens our knowledge of the phage communication system, a promising tool to fight antibiotic-resistant superbacteria.

Phages have a surprising social life. In 2017 it was discovered that they used a communication system called arbitrium, which they use to decide which life cycle they adopt after infection of their host, lytic or lysogenic. The lytic generates multiple copies of the virus within the bacteria, ending with the death of the infected bacteria (lysis) and thus releasing the phages. During the lysogenic cycle, the genetic material of the phage is integrated into the chromosome of the bacteria and thus, remaining quiescent, is copied and transmitted to the offspring when the bacteria replicates.

Until now it was believed that this arbitrium system worked only with two proteins and a small RNA. One protein is a regulator (AimR) and the other a signaler (AimP), which accumulates depending on the population (the more cells infected by phage, the more signaling). The production of small RNA (AimX) is decisive in deciding which life cycle the phage will follow.

“If there are few infected cells, there will be little signaling and a lot of RNA, so the phage begins the lytic cycle, generating many copies and lysing the bacteria so that the released phages can infect others,” Alberto Marina describes in a statement. CSIC research professor at the IBV and one of the main authors of the study.

On the contrary, “if there are many phages, and therefore a lot of signaling is generated, it is difficult for the new ones to find free bacteria and it is not convenient for them to multiply. Under these conditions it is better to integrate into the genome of the bacteria and remain quiescent until there is once again a high bacteria-phage ratio,” continues the Valencian researcher.

In his opinion, this is just the ‘tip of the iceberg’ of other more complex communication mechanisms between phages and bacteria. Now, together with researchers José R. Penadés (Imperial College London) and Avigdor Eldar (Tel Aviv University), Marina is developing the TalkingPhages project to delve deeper into these microbial communication systems.

Together with Wilfried J. J. Meijer, from the Severo Ochoa Molecular Biology Center (CSIC-UAM), the Marina and Penadés teams have just published a work in Nature Microbiology that reveals that the initial description of arbitrium presented a very simplified model.

“Now we have shown that more phage proteins and, above all, bacteria’s own proteins, are involved in the life cycle decision,” highlights Alberto Marina. In the updated model, “the decision between one life cycle or another is established through a complex network of antagonistic interactions involving phage proteins such as SroB, described in a previous article, and YosL, as well as a toxin-system. MazE-MazF antitoxin of the bacteria, which, in fact, is the key player in the decision.”

In summary, “the balance between all these proteins regulates the life cycle of the phage, which shows that this decision is highly complex and that it also requires the participation of the host,” maintains the IBV-CSIC researcher. “This would imply that the phage and its host have a deeper interrelationship and that phages are not selfish agents that only try to multiply at the expense of their hosts,” concludes Marina.

This is what they want to verify with the TalkingPhages project, which has received more than 8 million euros in one of the latest Synergy Grants from the European Research Council (ERC). They are now discovering the molecular basis of the arbitrium system in its context with the host cell.

The use of phages can have important biotechnological and biomedical utilities. In fact, it is one of the strategies being studied to fight antibiotic-resistant bacteria, known as superbugs, a pressing health problem that could become the first cause of death by disease in 2050 according to the World Health Organization. . Thus, intervening in the life cycle of phages could generate applications in the field of health in the medium or long term.