It's a well-known strategy in any war. While two forces are directly fighting against one another, the introduction of a third party ally can shift the dynamics towards one side. The new contingent not only distracts the targeted enemy but may even force them to forget about the initial war entirely. In the human context, this had led to numerous victories over the millennia and the beginning of the end of combat.
In infectious disease, a similar strategy has been employed to help tackle some of our worst infections. Antibiotics were the first and still are the go-to means of microbial distraction. However, in light of the continuing rise of antibiotic resistance, their usefulness is limited and we need to explore other options.
One such ally is a living organism known to have just as much of a hatred for infectious bacteria: the bacteriophage. Although known as a potential antimicrobial option for nearly a century; this small virus of bacteria is only now becoming darlings in the battle against infectious disease.
The main premise of phage incorporation into our attack against pathogens is simple: When an infection hits, these viruses can be introduced to occupy the bacterial defenses. As this struggle unfolds, the bacterium forgets about the human host, allowing the immune system to clear the infection. While this benefit is more than enough reason to explore the use of phages, research has revealed yet another fascinating benefit. In some cases, phages cause bacteria to not only forget about the human host, but also to lose the ability to cause infections altogether.
The first examples of such modifications came back in the 1970s in tests with E. coli. As it fought the phage attack, it changed. It looked different, acted different and grew much slower than expected. The best way to describe the bacterium was wounded. There was every indication phages could debilitate the target leaving it vulnerable to the immune system.
Other bacteria were tested over the next two decades including the cattle and human infection, Brucella abortus, the insect pathogen Bacillus thuringiensis, and one of the causes of foodborne disease, Listeria monocytogenes. While similar results were observed, there was a rather distressing outcome. The bacteria developed resistance against phage infection. The result suggested phages might be a great idea but only for short term use.
The phage proposition disappeared for a while until threats of a post-antibiotic era began to surface. In an attempt to find alternatives to antimicrobials, researchers returned to phages to find possibilities. As expected, some bacteria developed resistance but unbeknownst to the scientists, this was actually a good thing. By pressuring bacteria to become resistant, phages forced evolutionary changes in the pathogens rendering them harmless to us.
This new observation opened up a new direction. Phages could potentially be trained to be more aggressive and force bacteria to give up on their human hosts and focus on survival. While this seemed to be an excellent way to approach phage therapy, there was of course a problem with this direction. No one knew if this could apply in the real world.
Last week, the answer was found to be "yes." An international team of researchers revealed how phages of Vibrio cholera, the bacterium that causes cholera, could not only help the patient survive infection, but also render the pathogen incapable of causing human infection. The team focused on a species of bacteriophage known as ICP2, which had been isolated from recovering cholera patients in Bangladesh and Haiti.
The methods were fairly straightforward. The group first identified a number of phage-resistant bacteria and compared them at the molecular level to normal strains, known as wild-types. A number of changes were found, particularly in the makeup of two proteins. The first was found on the outer wall of the bacterium known as Outer Membrane Protein U (OmpU). The other was inside the cell and called the Cholera Toxin Transcriptional Activator (ToxR). OmpU helps the bacterium survive various different environments while ToxR controls the production of the deleterious cholera toxin.
When mutated bacteria were placed into the animals, the result was encouraging. Unlike normal cholera infection, which can be quick and drastic in nature, the mutants waned in their ability to infect. In the case of mutations to ToxR, the bacteria were incapable of causing infection altogether. In essence, by developing resistance to phages, cholera lost the ability to harm. In comparison to the Listeria results, this one revealed a greater potential in phage use.
The authors suggested this observation could offer a new life to the concept of 'third party' interventions in the fight against infectious disease. Though this was only a preliminary study, the door has now been opened to explore the use of phages, both natural and trained, to render some of our worst pathogens harmless. The process will no doubt take time and it will be years before we see any relevant medical interventions. Yet, as we face a never-ending war with pathogens such as cholera, and the post-antibiotic era continues to creep forward, the wait may be very well worth it.