Challenging the host narrow-band theory of phages

An electron microscope image shows how phages attach to a bacterial cell and inject their genome into the cell. Credit: Keystone-SDA

Viruses that infect bacteria could one day replace antibiotics because they precisely attack only certain pathogens. Now researchers at ETH Zurich show that this is not always the case. This new finding is important because bacterial viruses can pass on antibiotic resistance genes.

Phages – in short phages – are viruses that infect only bacteria. To capture a bacterial host, they first attach to certain molecules on the cell surface. Then they inject their genetic material into the bacterial cell. In order to reprogram the bacteria’s cellular machinery to produce new viral particles, phages must also outpace the target bacteria’s immune system.

Molecular entry points and the immune system differ from one bacterium to another, so it was generally thought that most phages have a narrow host range—that is, they infect only one type of bacteria or even a subtype. This also prompted the idea of ​​using natural bacteria killers to treat infections — especially when disease-causing bacteria acquire antibiotic resistance.

Now, however, a study led by Elena Gómez-Sanz, a research assistant in the group of Martin Loessner, Professor of Food Microbiology at ETH Zurich, challenges the host’s narrow range theory of phages. Phages within the Staphylococcus group of bacteria often infect multiple species simultaneously. The researchers recently published their findings in the journal Nature Communications.

Their findings could have direct consequences for phage therapy, which is not yet approved for use in Switzerland, but has long been used in Eastern Europe. Not only do phages kill bacteria, they can also transfer antibiotic resistance genes from one bacterium to another. Accordingly, the unexpectedly wide range of prey means that phages can spread their resistance genes into the environment much more than previously thought.

Many new phages have been isolated in wastewater

The mechanism by which sterilants can transmit antibiotic resistance among bacteria is already known. In short, when these viruses replicate in bacterial cells, they not only inject their genetic material into new virus particles; In some cases, they smuggle genetic material from infected bacteria – the resistance gene, for example – into virus particles. If one of these virus particles infects new bacteria, the resistance may be transmitted.

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Phages span a huge network of gene transfer within the staphylococcal species analyzed. The thicker the line between two types of bacteria, the more phages they have in common. Credit: Visualization: Göller et al. Nature Communications

This type of gene transfer has been well studied in staphylococci. This bacterial group, which includes more than 50 species, naturally colonizes not only humans, but also livestock, and is found in natural water bodies. The most famous member of this group is Staphylococcus aureus, a type of bacteria that naturally colonizes our nose and skin, but has recently evolved into a dangerous, multi-resistant pathogen.

It is widely believed that phages played a critical role in the evolution of the most common, widespread and multidrug-resistant pathogens. It is therefore not surprising that more than 90 percent of the known bacteriophages in staphylococcus originate from Staphylococcus aureus, usually isolated from clinical samples.

“However, if we want to assess the role of phages as vectors of antibiotic resistance, we have to look at the whole picture – not just the situation in human medicine,” says Gomez-Sanz.

Looking for as wide a range of natural staph phages as possible, ETH researchers visited wastewater treatment plants. After all, a great diversity of bacteria and their phages converge here – from human microbes, from animal husbandry, from households and industry. The researchers isolated a total of 94 phages from wastewater for their study.

Viruses span a giant network of gene transfer

The researchers conducted laboratory experiments to determine the natural pattern of prey from their isolated phages. To do this, they loosely placed phages on different potential host bacteria and studied their infection patterns. The 117 bacterial strains they studied in total included representatives of 29 different types of staphylococcus and bacteria from different habitats, with or without antibiotic resistance.

They found that a single phage infects, on average, four different bacterial species. Or, from the perspective of bacteria, “common” phages might enable one type of staphylococcus to exchange genetic material with, on average, more than 17 other species. “This massive network shows the huge impact that phages can have on bacterial communities,” says Gomez-Sanz.

Agents between good and evil

Several phages simultaneously infect a staphylococcal cell in an experiment. It’s entirely possible for someone to carry an antibiotic-resistant genome. Credit: Pauline Goller/ETH Zurich

The microbiologist says the narrow host-scale hypothesis may have survived for so long because there are hardly any previous similar studies looking at phage infection across many different bacterial species. Previous work has often been strictly limited to clinically relevant bacterial species such as S. aureus. However, the current study demonstrates the urgent need to investigate specifically the prevalence of antibiotic resistance beyond the scope of the individual biosphere.

“Human health is closely related to animal health and the environment,” says Gomez Sanz. The study underscores the importance of a modern “one health approach” to antibiotic use. The new findings on the network of individual natural phages, for example, show that phages can transfer antibiotic resistance from bacteria in animal microbes directly to human pathogens. This underscores the importance of the modern “one health approach” to antibiotic use.

It remains unclear how frequently resistance genes are spread

It is difficult to estimate how often phages transmit antibiotic resistance genes in nature from laboratory experiments conducted thus far. However, the current study assumes that none of the phages examined are particularly potent vectors.

For 28 of the 94 phages, the ETH researchers investigated how often they could take up the natural resistance gene while spreading phages in bacteria from the generated network. Absorption frequency varied from 1 in 100 particles to 1 in 10 million.

These huge differences are due to the different life cycles and enzymes that viruses use to package their genetic material. “Some are ‘more error-prone’ than others, which means they tend to include some bacterial genetic material in the package,” Gomez-Sanz explains. In addition, if these types of phages have a wide host range, the risk of transmission is greater.

As the authors stress, the study results are also important in terms of combating disease-causing bacteria in humans using phages. The finding that phages can have a wide host range should be considered as positive. This makes it easy to use against many different bacteria.

However, when phages are used in medicine, one must be careful that they do not also act as carriers of antibiotic resistance genes. It is therefore important to ensure that phages used in medicine have a dissemination mechanism that works as flawlessly as possible.

Fighting antibiotic resistance

more information:
Pauline C. Göller et al, a multispecies host group of staphylococcal phages isolated from wastewater, Nature Communications (2021). DOI: 10.1038 / s41467-021-27037-6

the quote: Challenge of the Host Narrow Band Theory of Phages (2022, January 17) Retrieved on January 19, 2022 from

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