The unexpected complexity of viruses that infect bacteria

Scientists have discovered that some phages (bacteriophage viruses, meaning they subsist on the bacteria they attack) determine their infection strategy and their life cycle through a communication system that is much more complex and complex than previously thought.

In work published in the journal Nature Microbiology, the research team shows that this communication system involves a complex network of antagonistic interactions between phage proteins and host bacteria. This discovery deepens our knowledge of the phage communication system, a promising tool for fighting antibiotic-resistant superbugs.

Phages have an amazing social life. In 2017, it was discovered that they used a communication system called an “arbitrium”, which they use to decide which life cycle they will adopt after infecting their host: lytic or lysogenic. The lytic creates multiple copies of the virus inside the bacteria, resulting in the death of the infected bacteria (lysis) and thus the release of the phages. During the lysogenic cycle, the genetic material of the phage is integrated into the chromosome of the bacteria and, thus, remaining in a dormant state, is copied and passed on to the offspring when the bacteria multiply.

Until now, this arbitration system was thought to work with only two proteins and a small RNA. One of the proteins is a regulator (AimR), and the other is a signaler (AimP), which accumulates depending on the population (the more cells infected with the phage, the more signaling). The production of small RNA (AimX) is critical when deciding which life cycle a phage will follow. “If there are few infected cells, there will be few signals 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,” describes Alberto Marina, a researcher at CSIC. Professor at the Institute of Biomedicine of Valencia (IBV) and one of the main authors of the study.

On the contrary, “if there are many phages and therefore many signals are generated, it is difficult for new bacteria to find free bacteria and it is difficult for them to reproduce. Under these conditions, it is better to integrate into the bacterial genome and remain dormant until the ratio of bacteria to phages becomes high again,” continues the Valencian researcher. In his opinion, this is just the tip of the iceberg of other, more complex mechanisms of communication between phages and bacteria. Marina is now developing the TalkingPhages project with researchers José R. Penades (Imperial College London, UK) and Avigdor Eldar (Tel Aviv University, Israel) to further explore these microbial communication systems.

Together with Wilfried J. J. Meyer of the Center for Molecular Biology of Severo Ochoa (CBM, CSIC and UAM), Marina and Penades’ teams have just published a paper in Nature Microbiology showing that the original description of arbitration was a very simplified model. “We have now shown that more phage proteins and, above all, the bacteria’s own proteins are involved in life cycle decisions,” emphasizes Marina. In the updated model, “the decision about one life cycle or another is established through a complex network of antagonistic interactions involving phage proteins such as SroB, described in the previous article, and YosL, as well as the toxin system. The bacterial antitoxin MazE-MazF, which is essentially a key player in the decision.”

Thus, “the balance between all these proteins regulates the life cycle of the phage, which shows that this decision is very complex and requires the participation of the host,” says the IBV scientist. “This would mean that the phage and its host have a deeper relationship and that phages are not selfish agents who try to reproduce only at the expense of their hosts,” Marina concludes. That’s what they want to test with the TalkingPhages project. They are now discovering the molecular basis of the arbitration system in its context with the host cell.

Recreation of a phage that infects a bacterium. (Illustration: Vicente Case Arrue/CSIC Comunitat Valenciana)

The use of phages may have important biotechnological and biomedical benefits. In fact, it is one of the strategies being studied to combat antibiotic-resistant bacteria known as superbugs, a pressing public health problem that could become the leading cause of disease-related deaths in 2050, according to the World Health Organization. Thus, interfering with the phage life cycle may have health applications in the medium to long term. (Source: CSIC)