Researchers have written another chapter in the textbook case of an arms race between a host and its pathogen. The main characters in this 70-year seesaw drama are the voracious European rabbit (Oryctolagus cuniculus) and a virus deliberately released in France and Australia to kill off the rabbits and protect fields and pastures. Working with museum specimens collected decades ago, a team has discovered that rabbits on two continents evolved the same genetic changes to beat back the virus—before the virus itself changed and regained the upper hand.
The find is a striking example of how evolution sometimes repeats itself, and it may hold clues to how human immune systems respond—or don't—to pathogens. The rabbit work, published online today in Science, "provides key new information on one of the greatest stories in evolution," says Edward Holmes, an evolutionary biologist at the University of Sydney in Australia who studies the biocontrol virus.
In Australia, a few dozen European rabbits introduced in the mid-1800s for hunters did what the animals famously do. They multiplied until hundreds of millions were chowing down on crops. So, in 1950, after a smallpoxlike virus found in South American rabbits turned out to kill the European relative, Australian authorities released the virus into the wild, cutting the rabbit population by 99%. A few years later, the virus, called myxoma, was released in France and eventually spread to the United Kingdom.
The result was "an opportunity to trace host-pathogen arms races right in front of our eyes," says Jia Liu, a biologist at the University of Arkansas for Medical Sciences in Little Rock. Within a decade, rabbit numbers were on the rise again as some evolved resistance to this deadly infection and the virus itself became less deadly.
To understand the rabbit's adaptations, Joel Alves, now an evolutionary biologist at the University of Oxford in the United Kingdom, evolutionary geneticist Francis Jiggins at the University of Cambridge in the United Kingdom, and colleagues tracked down specimens of U.K., Australian, and French O. cuniculus collected by museums prior to the virus's introduction. They sequenced all the genes and other DNA that might influence the body's immune defenses and compared the results with sequences from modern rabbits living in the same places. The comparisons revealed changes in many genes, usually a shift in the frequency of particular versions, or alleles, of a gene. Strikingly, half of the changes were shared by the rabbits in all three countries—evidence of parallel evolution.
One allele shift affected the rabbits' interferon, a protein released by immune cells that sounds the alarm about a viral attack and helps trigger an immune response. Compared with preinfection rabbits, modern rabbits make an interferon that is better at responding to the biocontrol virus, the researchers found when they added different versions of the protein to rabbit cell lines.
The virus has not stood still. In 2017, Holmes and his colleagues reported that in the 1970s the virus developed a greater ability to suppress the rabbit's immune responses. That change, as well as the natural emergence of another rabbit-killing virus, has caused populations to decline again. But in contrast to the parallel evolution in rabbits, myxoma viruses in the various locations took different genetic paths to regaining potency.
Andrew Read, an evolutionary microbiologist at Pennsylvania State University in State College, suggests the viral counterattack "is a cautionary tale" for researchers aiming to take charge of the evolutionary arms race by introducing biocontrol agents or making crops or livestock more resistant to disease. "One should be careful about evolution and counterevolution," he says. "The rabbit hasn't won."