Viruses that love to kill bacteria could help fight deadly infections

Viruses are often seen as threats, but some could be allies in the fight against disease. Scientists have long studied bacteriophages, viruses that attack and kill bacteria, as a possible solution to antibiotic resistance. These phages hijack bacteria, forcing them to produce more viruses until they burst.

Now, researchers are uncovering the secrets of a rare type of bacteriophage known as a jumbo phage, which may hold the key to developing powerful new antibiotics.

Jumbo phages are far larger than regular phages and use an intricate strategy to protect themselves. This strategy involves a unique protein shield that prevents bacterial defenses from interfering with their ability to reproduce.

A deeper understanding of how this shield works could lead to breakthroughs in medicine, particularly as antibiotic resistance continues to rise.

How viruses attack bacteria

Bacteriophages were discovered over a century ago. These viruses infect bacteria by injecting their genetic material inside, then hijack bacterial systems to reproduce.

Eventually, the bacteria become so packed with new viruses that they burst open, releasing more phages to continue the cycle.

Initially, scientists believed phages could be used to treat bacterial infections. Since they only target specific bacteria and leave human cells untouched, they seemed like a promising alternative to antibiotics. However, once antibiotics became widely available, interest in phage research declined.

Now, with antibiotic resistance becoming a global crisis, researchers are taking another look at these bacterial predators. Jumbo phages stand out as especially intriguing due to their size and complexity.

They contain more than four times the DNA of a typical phage, allowing them to create a special protected space inside bacteria. This unique defense system could make them more effective against resistant bacteria.

Protective shield of jumbo phages

One of the most fascinating discoveries about jumbo phages is their ability to create a protein-based shield inside infected bacteria. This shield forms a restricted space where the phage can safely copy its DNA, preventing bacterial defense mechanisms from attacking.

At UC San Francisco, researchers have been studying this process closely. They discovered that the shield functions through a series of molecular interactions they call “secret handshakes.” These interactions allow only certain proteins to enter the protected area, while others are blocked.

“This isn’t what we expected to see at all. It’s a surprisingly complicated thing for a phage to be doing,” said Dr Joseph Bondy-Denomy, associate professor of microbiology and immunology at UC San Francisco.

Rediscovering phage therapy

Jumbo phages are not a new discovery, but their complexity has only recently come to light. Scientists began studying them in the early 1980s, yet it wasn’t until 2017 that researchers at UCSF and UC San Diego identified the flexible protein that forms the protective shield.

In 2020, Dr. Bondy-Denomy and his team demonstrated that this shield prevents bacterial defenses from attacking the phage’s DNA. This discovery was a major step toward understanding how these viruses operate.

Graduate student Claire Kokontis, working with Dr. Bondy-Denomy, suspected that the shield might give jumbo phages an advantage over regular phages in medical applications. To test this idea, the researchers set out to determine how the shield recognizes which proteins to allow inside.

Their work revealed an unexpected system of interactions between proteins produced by the phage. These interactions ensure that only the right proteins can enter the protected space, giving the phage a significant survival advantage.

Secret handshake of jumbo phages

At the center of this discovery is a phage protein named Importer1, or Imp1. The researchers found that for any protein to enter the protected space, it must first interact with Imp1.

Further studies uncovered additional importer proteins that assist Imp1 in bringing outside proteins through the shield. The process is highly selective. If a protein interacts with Imp1 in the correct way, it is allowed inside. Otherwise, it is left out.

“It’s like a secret handshake between two friends. The ones that have the right handshake get the OK, and the others are tossed out,” said Dr. Bondy-Denomy.

To understand these handshakes at the molecular level, Kokontis mapped the surface of the Imp1 protein. The results showed that each phage protein allowed inside the protected area interacts with Imp1 differently.

One protein might touch the equivalent of a thumb, while another connects with a finger. This variety of interactions ensures that only the correct proteins are let through, making the shield an effective barrier against bacterial defenses.

Phage therapy and antibiotic resistance

The researchers conducted their experiments using Pseudomonas bacteria, which is notorious for its resistance to most antibiotics. The results suggest that understanding the shield’s molecular handshakes could help scientists improve an old method called phage therapy.

Phage therapy involves using viruses to treat bacterial infections. When a person is infected with antibiotic-resistant bacteria, phages can be introduced to attack and destroy the bacteria. However, bacteria evolve quickly, developing new defenses against both antibiotics and phages.

If bacteria find a way to bypass the phage’s protective shield, they could destroy the phage before it can reproduce. By understanding how the shield’s secret handshakes work, scientists can engineer phages that remain effective even as bacteria evolve new defense mechanisms.

Engineering viruses for medical use

Dr. Bondy-Denomy’s lab has already taken steps to modify these phages using CRISPR technology. By making precise genetic changes, scientists can strengthen the shield, ensuring that the phages can withstand bacterial counterattacks.

Beyond antibiotic resistance, researchers are exploring whether jumbo phages could be modified to produce drugs or fight infections linked to cancer. Their ability to selectively target bacteria while remaining harmless to human cells makes them an attractive option for medical applications.

“We’re just at the starting point of realizing all this potential,” Kokontis said. “By getting a handle on the basic science of how these phages work, we’re laying the groundwork to adapt them for fighting disease.”

New era of virus-based medicine

Jumbo phages have remained in the shadows of scientific research for decades, but their secrets are finally being uncovered.

Their complex shielding system and selective protein transport mechanisms set them apart from regular phages. As antibiotic resistance continues to threaten global health, these unique viruses could provide new hope.

Understanding their biology may open doors to revolutionary treatments, reviving phage therapy and offering solutions where antibiotics fail. Scientists are now at the forefront of harnessing nature’s own mechanisms to fight disease, turning one of bacteria’s greatest predators into a powerful ally.

The study is published in the journal Nature.

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