How Bacteria Survive a World Full of Killer Bacteriophages
Humans throughout history have invented a variety of ways to fight back against troublesome bacteria. But bacteria live in a dangerous world too. The human body and other bacteria-rich environments abound with bacteriophages, or viruses that prey upon bacteria. Phages can sometimes outnumber bacteria a hundredfold, yet the bacteria endure and even thrive. What gives?
New research from the Caltech lab of Sujit Datta, professor of chemical engineering, bioengineering, and biophysics, helps to explain why.
Among other work, Datta's lab studies bacterial chemotaxis: the movements of microbes in response to chemical stimuli, such as nutrients. To investigate this, the lab has devised experiments in which a dense colony of the gut bacteria Escherichia coli (E. coli), a commonly studied model organism, are deposited in a tube with a kind of "starting line," as in a race. Food—sugar plus an amino acid called L-serine that the bacteria find especially attractive—is placed nearby. As the bacteria begin to move toward the food, they form "these really cool fronts or coherent bands, almost like a peloton, a group of racers moving together in the Tour de France," Datta explains.
The team wondered whether this kind of experiment could help explain how bacteria escape phages in their normal environments, such as biological tissues and soils. But there was a problem. Such environments are complex, porous, and very difficult to see through. So, the team, led by Victoria Muir—then a postdoctoral researcher in Datta's lab and now an assistant professor at the University of Delaware—created the bacterial equivalent of an ant farm.
The transparent setup consists of a glass tube packed with tiny water-filled beads, or hydrogel, each a few times the size of an E. coli bacterium. When compacted, the beads form a solid mass, but one that is riddled with a maze of channels formed by the gaps between the beads. Bacteria added to the system have to navigate that maze, similar to how they swim through their natural soil environment, or, in the body, through materials like mucus. For the experiments, E. coli bacteria are genetically modified to glow green under fluorescent light, allowing their movements to be tracked. "We make environments that are structurally more akin to natural habitats of bacteria but are transparent, so we can actually watch the bacteria swimming through," Datta says.
To that experimental landscape, Muir added a variety of phages, creating a minefield for the bacteria to navigate. At first, the bacteria appeared to do ... nothing. They didn't move, leading the researchers to think, "Oh, okay, the phages won, that's the end of the story," Datta says.
But after a few hours, they kicked into gear. A line of bacteria took off in the direction of a food source, just as they had during experiments without phages. The more phages the researchers peppered into the field of play, the longer bacteria appeared to wait, sometimes as long as 15 hours, before they began to seek out food. But the bacteria managed to stay alive, even at phage concentrations that should have wiped them out.
The bacteria do not delay because they are hesitant of the phages: Bacteria have no way to sense their predators, and they behave the same whether the phages are there or not, Datta says. Rather, the wait is related to population recovery. Early on, bacteria are eating and growing, but the cells killed by phage infection cancel much of the population's growth. As a result, the microorganisms take far longer to reach a density at which they can form the "peloton." Once they do, however, chemotaxis—basically the group's hunt for food—is the key to their escape, allowing them to leave phages in the dust. "The bacteria move in a directed manner because they eat the food around them and so create the very gradient that draws them forward," Datta says. The peloton consumes the food around it, leaving a zone depleted of nutrients behind and an untouched supply ahead. The cells at the leading edge sense more food in front than behind, so the peloton swims in that direction.
Once the peloton is on the move, the phages can never catch up. Phages cannot swim but drift aimlessly, the way a drop of ink spreads in still water. Naturally, some bacterial cells do not win at this game of survival. The scientists spotted the remnants of cells infected by phages at the back of the group. But even though each bursting cell creates about 90 bacteriophages, viruses moving at random could not catch the group of bacteria steadily fleeing. Further testing showed that the bacteria evaded their phage predators without the need to evolve genetic resistance to them, which many biologists thought was necessary.
"The conventional paradigm is that chemotaxis enables the cells to access more nutrients and explore more terrain. Our work also suggests that it also helps them escape predation," Datta says. Indeed, inspired by the experiments, Alejandro Martínez-Calvo—another former postdoctoral researcher working with Datta and theory collaborator Ned S. Wingreen (BS '84) of Princeton University—created a mathematical framework for understanding how bacteria survive and how long it takes for a certain mass of bacteria to escape its phage predators, depending on the phage concentration and environmental conditions. More broadly, this work also illustrates a common axiom in nature (and the human world): There is strength in numbers.
"There's a saying: If you want to go fast, go alone, but if you want to go far, go as a group. To me, this is an interesting manifestation of that," Datta says.
The work is described in a paper in Science Advances titled "Death & Chemotaxis: Bacterial chemotaxis enables collective escape from phage predation." Datta's work was funded by the National Science Foundation, the Camille and Henry Dreyfus Foundation, the Pew Charitable Trusts, and the Princeton Catalysis Initiative.
Sujit Datta
