Some viruses, known as bacteriophages, only infect bacterial cells, often destroying those bacteria in the process. Bacteria, in turn, can develop defenses against these viruses. Bacteriophages or phages were once considered a promising treatment for bacterial infections before antibiotics came on the scene, making them unnecessary for further development. But as antibiotics have become less effective and bacteria evolve to resist their effects, scientists and in some cases, clinicians, have turned to bacteriophages as a potential treatment for bacterial infections once again.
Now, scientists have identified a bacteriophage that infects the pathogenic bacterium Legionella pneumophila, which causes Legionnaires' disease. This is the first example of such a phage, and it has provided new insights into how Legionella pneumophila evolved and causes disease. The study, which was reported in Science Advances, also showed that this novel phage, called LME-1, can infect Legionella pneumophila and reduce its growth in the cells that they infect–human macrophages.
"The Legionella field has been looking for phages for 50 years," said Alexander Ensminger, an associate professor at the University of Toronto. "We were doing all these things like looking in water samples, but all along there was one sitting in our freezer. We just had to figure out how to reveal itself as a phage."
The investigators had been intrigued by phages that infect Legionella because many Legionella use the CRISPR-Cas system to defend against these viruses. CRISPR-Cas may be well known as a gene editing tool, but it derives from a form of bacterial immunity. Bacteria use it to chop up viruses, and collect bits of the viral DNA that then get stored as a kind of memory of infection. Many Legionella bacteria carry genetic elements from LME-1.
The researchers had to find a way to trigger the production of LME-1 phages, which they did successfully. After much effort, they produced larger amounts of LME-1 so they could learn more about it and its relationship to Legionella. This work led to high-resolution images of the phage.
Next, the scientists found a type of bacterial cell that could be infected with LME-1; these cells often harbored mutations in a gene called lag1. They determined that lag1 can prevent LME-1 phages from attaching to cells by altering the surface of bacterial cells. When a bacterial cell carried the mutated lag1 gene, the phage was more likely to infect that bacterium.
Scientists have previously shown that 80% of all Legionnaires' disease cases are caused by strains of Legionella that carry the lag1 gene. The lag1 gene, when functioning normally, seems to also prevent the immune system from destroying the bacterial pathogen. The bacterium’s defense against the LME-1 phage may have spurred the virulence of Legionella in people.
While Legionella likely acquired this gene as it evolved immunity from phages, it has also provided the pathogen with greater protection from the human immune system.
Now the team wants to find other phages that may work as a treatment for Legionnaires’. It also highlights the importance of fully understanding phages before they are deployed as a treatment.
"Our study is also a cautionary tale that, with phage therapy, we need to understand the relationship between phage and bacteria before we deploy it, because in some instances, resistance to the phage might make the bacteria more harmful to humans," Ensminger noted.
Sources: University of Toronto, Science Advances