Ancient viruses hidden inside bacteria could help defeat modern infections

The researchers studied bacteria that carry extremely old, inactive viruses and found that these dormant invaders still play a protective role. Their findings, published in Nucleic Acids Research, suggest that this defense system could eventually help design stronger antiviral methods for use in medicine and food safety.

"There's been a flurry of discoveries in the past few years related to antivirus systems in bacteria," said Wood, who led the project. "Antibiotics are failing, and the most likely substitute is viruses themselves. Before using viruses as antibiotic replacements to treat human infections, however, we must understand how the bacterium defends itself from viral attack."

How Dormant Viruses Help Bacteria Fight Back

According to Wood, scientists have long known that ancient, inactive viruses known as cryptic prophages can insert their genetic material into bacterial DNA. These genetic fragments allow bacteria to use specialized enzymes and proteins to prevent new viruses, called phages, from infecting the cell.

In this new study, the Penn State team found that a protein called recombinase (an enzyme that cuts and reconnects DNA strands) can modify bacterial DNA in response to viral threats, but only if a prophage is already embedded in the genome. This recombinase acts as a rapid-response defender when the cell detects danger.

The specific recombinase identified in this system is known as PinQ. When a virus approaches the bacterial cell, PinQ triggers a DNA inversion, flipping a section of genetic code inside the chromosome. This change creates two "chimeric proteins" composed of DNA from the prophage itself. Together, these proteins -- collectively called Stf -- block the virus from attaching to the bacterial surface and injecting its genetic material.

"It's remarkable that this process actually produces new chimeric proteins, specifically from the inverted DNA -- most of the time when you change DNA, you just get genetic mutations leading to inactive proteins," Wood said. "These inversions and adaptations are clear evidence that this is a fine-tuned antivirus system that has evolved over millions of years."

Implications for Antibiotic Resistance and Antiviral Research

The growing threat of antibiotic-resistant infections is partly due to the overuse of antibiotics, Wood explained. Viruses could offer a safer alternative because they target specific bacterial strains without harming others and evolve alongside their hosts. Understanding this natural bacterial defense could help researchers harness it to develop more precise treatments and reduce antibiotic dependence.

Although recombinase enzymes were previously detected near bacterial defense regions, this is the first study to show that they directly participate in virus defense.

"It's not that researchers missed these enzymes, it's that they saw them and overlooked them as mere markers of virus genes," Wood said. "To defend against viruses, bacteria must have many different defense systems, and this is just yet another example of one of those systems."

Testing the Ancient Defense System

To explore how this mechanism works, the team increased the production of Stf proteins in E. coli bacteria and then introduced viruses to the sample. After leaving the mixture overnight, they measured its turbidity, or cloudiness, to see whether the viruses had successfully infected the bacteria. The cloudier the solution, the fewer active viruses remained.

They also used computer models to simulate how viruses attach to bacterial surfaces, a process known as adsorption, confirming the accuracy of their simulations by comparing them to lab results.

"When we overproduce the protein, we initially stop the virus from landing on the cell surface," Wood said. "After eight experimental iterations, however, the virus changes its landing proteins -- how it identifies and attaches to the bacteria -- and can get by this defense."

Broader Benefits for Food and Health

This research has improved the team's understanding of how antivirus systems operate, Wood said, which can help them more effectively cultivate the bacteria used to ferment foods like cheese and yogurt, as well as improve how bacterial infections are managed in health care settings. Looking forward, Wood said the team plans to continue researching the antivirus applications of eight additional prophages currently in their lab.

"This is a story about how a fossil protects its host from the outsider, and we have 10 other fossil-related stories that could offer their own defenses waiting to be tested," Wood said. "Having a greater understanding of how these viruses interact with bacteria will give us incredible insight on how to effectively and safely harness bacteria in bioengineering."

Other co-authors include Joy Kirigo, who recently received her doctorate in chemical engineering from Penn State; Daniel Huelgas-Méndez, a chemical engineering doctoral candidate from the National Autonomous University of Mexico (UNAM) who conducted a research stay at Penn State; Rodolfo García‐Contreras, a professor of microbiology at UNAM and adviser to Huelgas-Méndez; María Tomás, coordinator of the Genomic Diagnosis Unit at the University Hospital of A Coruña; and Michael J Benedik, Regents Professor of Biology at Texas A&M University.

This research was supported by the Biotechnology Endowment, the National Autonomous University of Mexico and the Secretariat of Science, Humanities, Technology and Innovation.