An international team led by the Institute of Biomedicine of Valencia (IBV-CSIC) and Imperial College London, with the participation of CEU Cardenal Herrera University, has demonstrated that phages, or bacteriophages—viruses that infect bacteria—can develop interspecies social behaviors through small messenger molecules called peptides. The results, published in the journal Cell, show for the first time that peptide communication is not limited to phages of the same lineage or species, but also functions between different species, allowing viruses to coordinate fundamental decisions for their collective survival.

Although it was already known that simple organisms like bacteria use communication systems, the discovery that viruses also do so is relatively recent, and until now it was assumed that they were only capable of responding to signals from their own species. The new work breaks this paradigm by demonstrating for the first time that phages can recognize and respond to peptide signals produced by unrelated viruses. “The discovery of this phenomenon, called cross-talk, has allowed us to confirm that certain peptides bind with high affinity to receptors of unrelated phages, activating or deactivating pathways that determine whether the virus will follow a lytic or lysogenic cycle,” explains Alberto Marina, a researcher at the IBV-CSIC who leads the study and coordinates the CSIC Antimicrobial Resistance Connection.

The concepts of lysis and lysogeny describe the two strategies bacteriophages use to infect bacteria. In the lytic cycle, after infecting the bacterium, the phages multiply rapidly until they destroy the infected cell. In the lysogenic cycle, the viral genome integrates into the bacterium without damaging it, remaining dormant for generations. Viruses in a lysogenic state can receive an activating signal and enter the lytic cycle, destroying the host cell in a process known as induction.

In mixed cultures—laboratory experiments where different types of viruses coexist in the same environment—the research team has observed how the common language shared by phages modifies the dynamics of lysogeny and induction. Therefore, the cross-communication discovered in this work represents an essential tool in the decisions that phages make collectively to ensure their survival.

The work also demonstrates that cross-communication can develop between bacteriophages that infect different bacterial species, which has significant implications for understanding how microbial communities function. In other words, the language shared by viruses is so universal that it allows a ‘phage A’ to communicate with a ‘phage B’ to coordinate infection strategies, even if each decides to infect a different bacterium. “The structural data reveal that minimal changes, such as a single mutation in a peptide, can activate or block communication, generating different dialects of this language that only a group of phages understands. This suggests a very fine evolutionary mechanism for modulating these interactions,” explains Dr. Francisca Gallego del Sol, a researcher at the IBV-CSIC and first author of the study.

To decipher this language and confirm that different viruses communicate with each other, the team used a multidisciplinary approach that combines structural biology techniques using X-rays and biophysical analyses performed at the IBV-CSIC, along with experiments with genetically modified viruses in cell cultures carried out at Imperial College London and CEU Cardenal Herrera University. Thanks to this combination of methods, it has been possible to understand how this communication works, from the atomic level to its potential consequences for the ecosystem.

The finding represents a true paradigm shift by demonstrating that phages can communicate with viruses that are neither descendants of nor belong to the same species. According to the authors, this ability opens the door to the study of social behavior among phages and suggests that viral communication in natural environments could play a much broader role than previously imagined. Furthermore, understanding how these viruses communicate could lead to the development of tools for controlling bacterial communities by manipulating their shared molecular language.

The work, which provides a comprehensive view of the phenomenon through an approach that combines biochemistry, structural biology, genetics, microbial ecology, and evolutionary modeling, represents the starting point for the TalkingPhages project, funded by a selective Synergy Grant from the European Research Council (ERC).

Future Applications of Cross-Communication

The authors emphasize that deciphering how phages communicate to infect bacteria will allow for the design of new tools useful in therapeutic or biotechnological strategies by disrupting or modifying the language shared by these viruses.

“This could lead to the development of new antibacterial strategies by manipulating viral communication signals; or to the design of intelligent therapeutic phages capable of changing their behavior according to the signals present in an infection. Furthermore, it could be used to control industrial, environmental, or clinical microbiomes by modulating communication between bacteria and phages; and to develop future biotechnological tools based on peptides capable of activating or silencing phage populations,” explain the researchers from the IBV-CSIC.

In short, the study strengthens our knowledge of phage communication, behavior, and evolution, which will allow for a better understanding of how microbial communities evolve, including their impact on pathogens or resistance to traditional antibiotics.

CELL