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Could A Bacteria-killing Virus Help Solve Antibiotic Resistance?

Jumbo phages belong to a group of viruses that attack bacteria. They inject their DNA and then reproduce by taking over the cell's DNA-copying machinery. Eventually, a phage makes so many copies of itself that it will burst bacterial cell it has infected.

Scientists have known for a while that a jumbo phage pulls off its attack and escapes the bacteria's defenses by surrounding its DNA with a protective shield made of protein. But how the shield recognizes certain useful molecules and allows them to pass in while keeping harmful ones out has been a mystery.

Now, research from UC San Francisco, published Feb. 5 in Nature, shows that the protein shield works via a set of "secret handshakes," allowing only a specific set of useful proteins to pass through. The handshakes involve a large, central protein capable of using different parts of itself — like the fingers on a hand — to screen other proteins and grant them passage or not, thereby keeping out the bacteria's defenses.

"This isn't what we expected to see at all," said Joseph Bondy-Denomy, Ph.D., associate professor of microbiology and immunology at UCSF and senior author of the study. "It's a surprisingly complicated thing for a phage to be doing," he said.

Scientists hope the discovery can help them learn how phages might be used to make new antibiotics that can address the growing crisis of resistance.

Secret handshakes

Jumbo phages belong to a group of viruses called bacteriophages, or phages for short, which were discovered more than a century ago. Initially, phages were seen as a way to treat bacterial infections, because they are harmless to humans and can kill specific bacteria while leaving others alone. Interest died away once antibiotic drugs were developed, but today's urgency to find new ways of fighting antibiotic-resistant bacteria has sparked new research.

Scientists first began working on jumbo phages in the early 1980s but it wasn't until 2017 that researchers at UCSF and UC San Diego worked together to identify the flexible protein that makes up the shield. In 2020, Bondy-Denomy led a study showing that the protein shield protects the phage's DNA from attacks by the bacteria's defenses. He and Claire Kokontis, B.S., a graduate student, suspected this shield may give jumbo phages distinct advantages over regular phages when it comes to using these viruses against infections.

The researchers wanted to learn how the shield recognizes bacterial proteins the virus needs to copy its DNA so it can give them passage into the protected area. The secret, they discovered, was a group of proteins made by the phage that interact in an unexpected way. At the center was a phage protein Kokontis called Importer1, or Imp1. For proteins to be imported into the protected space, they had to interact with Imp1.

Living Pseudomonas bacteria infected by jumbo phages. The bright spots show the "handshaking" protein, Imp1, that is essential for preventing harmful proteins from getting through the protective shield around the phage's DNA. Image by Bondy-Denomy Lab

The researchers also found an additional set of importer proteins that assist Imp1 in bringing outside proteins through the shield. The interaction between Imp1 and a protein outside the shield needs to be just right before the protein gets the go-ahead to enter the protected area.

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

To see exactly what those handshakes looked like, Kokontis mapped the surface of the Imp1 "hand" at the molecular level. The map revealed that each phage protein that is allowed into the protected area has its own unique way of interacting with the Imp1 hand – one protein touches a thumb, another a finger, another a different finger. This variety of combinations allows the group of importer proteins to recognize an array of handshakes.

A new way of making antibiotics

The researchers did their work using Pseudomonas bacteria, which they chose because it is notorious for its resistance to most antibiotics.

What they learned will help scientists improve on an old approach that was left behind once antibiotics became standard. Called phage therapy, it involves fighting one infection with another. First a human gets infected by bacteria. Then the human uses a phage to infect and kill the bacteria.

By getting a handle on the basic science of how these phages work, we're laying the groundwork to adapt them for fighting disease.

Clair Kokontis, B.S.

But bacteria are quick to evolve new defenses. Once they have devised a way to get past the phage's protective shield, they will kill the phages. Understanding exactly how the shield's secret handshakes work will help scientists engineer phages that can withstand these evolutionary changes.

Bondy-Denomy's lab has already developed a CRISPR-based, gene editing method to make the necessary genetic changes to these jumbo phages. Scientists can also employ that knowledge and ability to engineer jumbo phages that produce drugs or fight cancers caused by bacterial infections.

"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."

Authors: Other authors of this study are Timothy Klein and Sukrit Silas of UCSF

Funding: This work was funded by the NIH (grants R01 AI171041 and R01 AI167412).

A Shocking Link Between Gut Bacteria And Alzheimer's

A groundbreaking discovery has unveiled an unexpected connection between a common gut bacterium and the progression of Alzheimer's disease, potentially reshaping medical understanding of this devastating condition. Research suggests that gut bacteria, particularly a strain commonly found in hospital settings, may contribute to cognitive decline in ways previously overlooked.

This revelation highlights the delicate balance within the microbiome and raises new concerns about the long-term impact of antibiotics and hospital-acquired infections. While researchers caution that more studies are needed, these findings suggest that the path to brain health may begin in the gut.

The hidden danger inside the gut

Scientists have long suspected a connection between gut health and neurological disorders, but this new study provides direct evidence of how gut bacteria can influence brain function. The research focuses on a specific bacterium, typically considered harmless, that can become a potential threat under certain conditions, especially in hospital environments.

When the gut microbiome is disrupted, often due to antibiotic use, this bacterium can multiply unchecked, enter the bloodstream, and reach the brain. Once there, it triggers inflammation and other biological responses associated with neurodegenerative diseases. These findings suggest that Alzheimer's disease may not solely originate in the brain but could be influenced by imbalances in gut bacteria.

Hospitals as an unexpected risk factor

Hospitals, while essential for treating illnesses, may also serve as breeding grounds for harmful bacteria. This study highlights the risks of hospital-acquired infections, particularly for elderly patients who are already vulnerable to cognitive decline.

When patients receive antibiotics for unrelated infections, the medication often kills off beneficial gut bacteria, allowing harmful strains to thrive. This process sets off a chain reaction that enables bacteria to move beyond the digestive system and potentially impact brain health. As researchers continue to investigate this link, healthcare providers may need to reconsider how antibiotics are used, particularly in older patients and those at higher risk of neurodegenerative diseases.

How gut bacteria reach the brain

The study used mouse models to trace how gut bacteria could impact brain health. Antibiotic treatments disrupted the natural balance of gut bacteria, allowing a particular strain to flourish. The bacterium then migrated into the bloodstream and crossed the blood-brain barrier, which is supposed to protect the brain from harmful invaders.

Once inside, the bacteria triggered an immune response, leading to inflammation and damage to brain cells. Over time, this process mirrored the progression of Alzheimer's disease, raising the possibility that bacterial infections may accelerate cognitive decline. These findings challenge conventional thinking about neurodegenerative conditions and suggest that gut health could be a crucial factor in prevention and treatment.

What this means for Alzheimer's prevention

The potential link between gut bacteria and Alzheimer's opens up new possibilities for treatment and prevention. Scientists are now considering ways to regulate the microbiome to protect brain function. One approach involves probiotic therapies designed to restore gut balance. If harmful bacteria can be kept in check, it may reduce the risk of inflammation-related damage in the brain.

Another avenue of research focuses on antibiotic alternatives that preserve beneficial bacteria while targeting harmful strains. Since hospital-acquired infections pose a potential risk, stricter infection control measures could also play a role in protecting patients. Dietary strategies that support a healthy gut microbiome, such as fiber-rich foods and fermented products, may be another way to maintain the delicate balance needed for overall well-being.

The future of Alzheimer's research

This discovery signals a shift in how scientists approach Alzheimer's disease. Instead of focusing solely on brain function, researchers are now exploring the broader role of gut health in neurodegeneration. The next phase of research will likely expand to human studies, investigating whether similar patterns occur outside of controlled lab conditions.

If these findings hold true in clinical trials, it could lead to significant changes in medical protocols. Physicians may begin screening patients for gut imbalances, developing personalized interventions to prevent harmful bacteria from spreading. Adjustments to antibiotic use and infection prevention strategies may become standard practices in hospitals, particularly for aging populations.

Understanding the relationship between the gut and the brain could revolutionize how neurodegenerative diseases are treated. By addressing the root causes of inflammation and bacterial migration, scientists may be able to slow or even prevent cognitive decline. As more research unfolds, the connection between gut bacteria and Alzheimer's could prove to be one of the most important breakthroughs in modern medicine.

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