Viruses that infect bacteria may have a life cycle that scientists had not previously been aware of. The discovery is now prompting researchers to rethink how bacterial viruses are used – both in agriculture and in developing new treatments for people.
Scientists have long known that bacteriophages (phages) – viruses that infect bacteria – can live inside bacteria in different ways: some are aggressive and kill the bacteria from within, whereas others coexist more peacefully with their host.
Now, a new study based on both experimental observations and genetic analyses shows that this division is not sufficient – phages can also have a third type of life cycle.
The discovery is fundamental science, but it reshapes the framework researchers rely on – including when they attempt to use phages in practice.
“All over the world, research is being carried out into how phages can be used to control bacteria,” says Lars Hestbjerg Hansen, Professor, Department of Plant and Environmental Sciences, University of Copenhagen, Denmark.
This applies both to agriculture, in which researchers are investigating whether phages can be used to combat bacteria that attack crops such as wheat, oats and barley, and to research into bacteria that infect people.
“This study improves our understanding of how phages can live – and that has implications for how we can use them industrially or pharmaceutically.”
The research has been published in Nature Microbiology.
Phages no longer fit into two boxes
In broad terms, phages are understood to live in two basic ways.
Some phages are virulent, meaning that they infect bacteria and force them to produce new phage components until the bacterial cell becomes so packed with virus particles that it eventually bursts – releasing the phages, ready to infect new bacteria.
In short: the bacteria die.
Temperate phages, by contrast, can peacefully coexist with the bacterium in a lysogenic infection cycle, in which the virus’s genetic material is incorporated into the bacterium’s own DNA. No new virus particles are produced, and the bacterium survives.
The temperate phages may later excise themselves from the bacterial genome again if the bacterium becomes stressed.
The discovery was made while Lars Hestbjerg Hansen and colleagues were experimentally investigating how phages manipulate microbial communities in wheat plants as part of the MATRIX project.
Phages play a key role in microbial ecosystems by killing certain bacteria and enabling others to survive. Here, the researchers encountered something unexpected: phages that did not fit neatly into either category – but instead combined traits from both.
“The goal is to use phages for biocontrol of, for example, bacteria that infect potatoes, or as therapies for humans. In our research, we found some very large phages that did not resemble other known phages and that behaved like virulent phages, while at the same time behaving ‘unusually’,” says Lars Hestbjerg Hansen.
Hundreds of newly discovered phages
To learn more about the new phages, the researchers searched a range of databases to see which viruses the large phages most closely resembled.
They found that the phages in question actually resembled fragments of bacterial DNA from bacterial isolates and therefore appeared more closely related to temperate phages – despite behaving as virulent phages.
In other words, they combined features from both of the known life cycles: they can kill some bacteria while continuing to live in others.
To test whether the discovery was a rare exception or a widespread phenomenon, the researchers combed through independent databases containing more than 270,000 genome sequences from Escherichia coli bacteria.
The researchers identified 373 phage strains that infect E. coli and live in this previously unknown way – a scale that makes it difficult dismiss the finding as a curiosity.
They also identified 285 phage strains that live in the same way but infect other bacteria.
“Our findings challenge the prevailing view of the phage life cycle as a simple dichotomy, and we can also see that many phages have this type of life cycle,” says Lars Hestbjerg Hansen.
Allows one daughter cell to survive
Further studies of how phages infect bacteria gave the researchers a clearer picture of this previously unknown life cycle.
The research showed that these phages do not integrate their genome into the bacterial genome in the same way as temperate phages. Instead, they localise to a specific region within the bacterial cell.
When the bacterium divides, the phage ends up on one side of the cell and therefore follows only one daughter cell – not the other.
In this way, the phage solves its own problem: the host population is preserved, enabling the phage to persist in the system without exhausting its own resource – consistent with patterns researchers observe across bacteria.
“Viruses typically develop strategies over time that keep their host alive and active. If a virus consistently kills its host, it quickly runs out of new bacteria – and dies itself. A better strategy is therefore to keep the host alive – in this case by allowing one daughter cell to escape infection,” says Lars Hestbjerg Hansen.
On keeping your tongue straight
Lars Hestbjerg Hansen therefore stresses that the discovery is not inherently a new technology – but that it changes what researchers should expect when working with phages in the future.
If, for example, the aim is to kill bacteria that interfere with wheat production, it will probably be necessary to choose a phage that does so efficiently.
In such cases, one would typically prefer a virulent phage. But anyone assuming that the newly discovered giant phage is effective at killing bacteria will be sorely disappointed: it prefers to live alongside its host without killing it – even though it shares many characteristics with virulent phages.
“It also works the other way around. We have often looked at genetic material and assumed that it came from temperate phages because they live together with bacteria, when in fact they may also behave like virulent phages. This should prompt other researchers to revisit and review their strain collections to determine whether a virulent phage may have been acquired inadvertently,” concludes Lars Hestbjerg Hansen.
