Bacteria can be friends and foes—causing infection and disease, but also helping us slim down and even combating acne. Now, a new study reveals that viruses have a dual nature as well. For the first time, researchers have shown that they can help our bodies fight off invading microbes.
"This is a very important story," says Marilyn Roossinck, a viral ecologist at Pennsylvania State University, University Park, who was not involved in the work. "We don't have all that many examples of beneficial viruses."
One of our most important lines of defense against bacterial invaders is mucus. The slimy substance coats the inside of the mouth, nose, eyelids, and digestive tract, to name just a few places, creating a barrier to the outside world.
"Mucus is actually a really cool and complex substance," says Jeremy Barr, a microbiologist at San Diego State University in California and lead author of the new study. Its gel-like consistency is thanks to mucins, large, bottle brush-shaped molecules made of a protein backbone surrounded by strings of sugars. In between the mucins is a soup of nutrients and chemicals adapted to keep germs close, but not too close. Microbes such as bacteria live near the surface of the layer, whereas the mucus at the bottom, near the cells that produced it, is almost sterile.
Mucus is also home to phages, viruses that infect and kill bacteria. They can be found wherever bacteria reside, but Barr and his colleagues noticed that there were even more phages in mucus than in mucus-free areas just millimeters away. The saliva surrounding human gums, for example, had about five phages to every bacterial cell, while the ratio at the mucosal surface of the gum itself was closer to 40 to 1. "That spurred the question," Barr says. "What are these phages doing? Are they protecting the host?"
To find out, Barr and his colleagues grew human lung tissue in the lab. Lungs are one of the body surfaces that is protected by mucus, but the researchers also had a version of the lung cells where the ability to make mucus had been knocked out. When incubated overnight with the bacterium Escherichia coli, about half the cells in each culture died; the mucus made no difference to their survival. But when the researchers added a phage that targets E. coli to the cultures, survival rates skyrocketed for the mucus-producing cells. This disparity shows that phages can kill harmful bacteria, Barr says, but it's not clear whether they help or hurt beneficial bacteria; that may depend on which types of phages are present.
In a related series of experiments, the team found that the phages are studded with antibodylike molecules that grab onto the sugar chains in mucins. This keeps the phages in the mucus, where they have access to bacteria, and suggests that the viruses and the mucus-producing tissue have adapted to be compatible with each other, the team reports online today in the Proceedings of the National Academy of Sciences.
Mucus-covered surfaces aren't unique to our insides; the slime can be found throughout the animal kingdom. It protects the whole bodies of fish, worms, and corals, for example. Protective phages seem to be equally widespread: Barr and his colleagues found dense populations of phages in every species they sampled. "It's a novel immune system that we think is applicable to all mucosal surfaces, and it's one of the first examples of a direct symbiosis between phages and an animal host," Barr says.
In this study, the researchers chose the phage and the bacterium, but it's possible that the animal host selects specific phages to control specific types of bacteria, such as by outfitting mucins with particular sugars that those phages recognize. The next step, Barr says, is to explore how this symbiosis works in real-life mucosal surfaces of all types, where many different types of phages and bacteria are interacting.
"This is a novel take on the whole microbiome-host relationship," adds Michael McGuckin, a mucosal biologist from Mater Research, a medical research institute in South Brisbane, Australia, who was not involved in the work. The finding, he says, could provide insights into conditions such as inflammatory bowel disease (IBD). We all have an ecosystem of hundreds of bacterial species in our gut, but patients with IBD have a disrupted ecosystem with different dominant species. These diseases, which include Crohn's disease and ulcerative colitis, also involve a breakdown in the mucus lining of the gut, he says, and this new study suggests that a failure in phage-based immunity might be the link between those symptoms.
McGuckin is intrigued by the idea that phages may help select the types of bacteria that live inside us. "There's tons of questions around just how this whole system might control microbial populations in the gut, which have increasingly been shown to be important in obesity and diabetes, and all sorts of human conditions."
It may also be possible to design a mucus-compatible phage that could fight infection or alter the body's microbial balance, although that possibility is still very distant. This work, Barr says, "forces us to reevaluate the role of phages. Hopefully this will get people thinking about what they do and how we can use them to help us and combat disease."