Scientists have discovered that some viruses can deliberately generate genetic diversity to evade bacterial defenses, a finding that could point to new approaches for treating infections when antibiotics fail.
Viruses that selectively infect and kill bacteria—known as bacteriophages, or simply phages—infect bacterial cells without harming human cells. After attaching to a bacterial cell, they inject their genetic material into it, hijack the cell’s machinery and force the bacterium to produce new phages until the cell eventually bursts.
The problem is that bacteria can develop defenses against phages in much the same way as they develop resistance to antibiotics.
A new study shows that phages have their own evolutionary countermeasure.
Some viruses found in the human gut can rapidly generate genetic diversity among their offspring, increasing the chances that at least some of the viruses will survive a bacterial counterattack, according to research published in Nature Microbiology, Euronews reports.
The discovery could point to a new avenue for developing alternatives to antibiotics amid the growing number of difficult-to-treat, drug-resistant infections.
Researchers at Michigan State University identified previously underestimated regions in bacteriophage genomes that act as genetic “hotspots,” allowing the viruses to repeatedly alter key genes as they reproduce.
This suggests that these regions help phages evolutionarily safeguard themselves against bacterial defenses. Rather than producing genetically identical copies, they generate diverse offspring with different characteristics, increasing the likelihood that some of the viruses will retain the ability to infect and kill their bacterial hosts.
“This changes our understanding of how phages evolve,” said study co-author Chris Waters, a researcher in Michigan State University’s Ecology, Evolution and Behavior program, in an interview with EurekAlert. “Instead of simply taking over their hosts and mass-producing exact copies of themselves, they actually use these mutation hotspots to create an entire zoo,” he added, explaining that phages are essentially “hedging their bets.”
The scientists studied T2 bacteriophage, which infects E. coli, after investigating a bacterial defense system capable of recognizing and destroying the DNA of invading phages.
The team transferred this defense system into laboratory strains of E. coli and exposed the bacteria to phages. However, the protection proved short-lived. Within just a few hours, the phages began overcoming the bacterial defense.
“Within a few hours, the phages would always start to take over,” Waters recalled. “We couldn’t understand why.”
When the researchers sequenced the viruses that had become resistant to the defense system, they found recurring mutations in a gene called agt, particularly in a region containing repetitive DNA. “When I saw the data, I thought, ‘Oh my God,’” Waters said.
The region turned out to be what scientists call a contingency locus—a highly mutable area where the DNA-copying mechanism can make errors while replicating repetitive sequences.
As a result, a reversible frameshift mutation occurs, changing the way the gene’s instructions are read.
In some phages, an additional repeat appears, while in others, one of the repeats disappears. This ultimately produces a population containing different variants of the same virus, potentially with different abilities to evade bacterial defenses.
The researchers found that mutations accumulated in these repetitive regions thousands of times faster than elsewhere in the phage genome.
And this mechanism is not limited to a single virus.
Using experimental evolution and genome sequencing techniques, the scientists identified similar contingency loci in T4 phage, which also infects E. coli. They also found that simple repetitive sequences are widespread among different E. coli phages, although their numbers vary depending on the functions of the genes involved.
The study comes amid intensive efforts by scientists and policymakers to find alternatives to antibiotics.
Phage therapy is not a new idea. Phages began being used to treat bacterial infections as early as the 1920s, but interest in the approach declined after antibiotics such as penicillin became widely available.
Now, as antimicrobial resistance continues to rise, interest in phage therapy is returning.
Part of the appeal of phages lies in their selectivity. While many antibiotics destroy beneficial bacteria along with the bacteria targeted by treatment, individual phages can be highly specific to particular bacterial species or even strains.
But that same specificity is also a weakness: bacteria can develop resistance to a particular phage, rendering the therapy ineffective.
The Michigan State researchers’ findings suggest that scientists may eventually be able to harness the viruses’ own evolutionary strategies to make phage therapy more resilient.
“If we can harness these kinds of evolutionary tricks, we may be able to develop more effective phage therapies in response to the antibiotic resistance crisis,” Waters said.
“We will never be able to completely eliminate resistance,” he added. “But if we better understand how bacteria defend themselves against phage infection and how phages respond, we may be able to minimize it.”
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