With the global Covid death toll falling to its lowest level since the first weeks of the pandemic in 2020, it may be tempting to conclude that the coronavirus is becoming irrevocably milder. This notion fits with the widely held belief that all viruses start out bad and inevitably evolve to become gentler over time.
“There was this dominant narrative that natural forces are going to solve this pandemic for us,” said Aris Katzourakis, an evolutionary biologist at the University of Oxford.
But there is no such law of nature. The evolution of a virus often takes unexpected twists and turns. For many virologists, the best example of this unpredictability is a pathogen that has been plaguing rabbits in Australia for 72 years: the myxoma virus.
Myxoma has killed hundreds of millions of rabbits, making it the deadliest vertebrate virus known to science, said Andrew Read, an evolutionary biologist at Pennsylvania State University. “It’s absolutely the greatest carnage of any vertebrate disease,” he said.
After its introduction in 1950, myxomavirus became less lethal to rabbits, but Dr. Read and his colleagues discovered that it reversed course in the 1990s. And the researchers’ latest study, published this month, found that the virus appears to be evolving to spread from rabbit to rabbit even faster.
“It’s still getting new tricks,” he said.
Scientists intentionally introduced the myxoma virus to Australia in hopes of wiping out the country’s invasive rabbit population. In 1859, a farmer named Thomas Austin imported two dozen rabbits from England to hunt on his farm in Victoria. With no natural predators or pathogens to hold them back, they reproduced by the millions and ate enough vegetation to threaten native wildlife and sheep farms across the continent.
In the early 1900s, researchers in Brazil offered Australia a solution. They had discovered the myxoma virus in a species of cottontail rabbit native to South America. The virus, which is spread by mosquitoes and fleas, hardly harmed the animals. But when the scientists infected European rabbits in their lab, the myxoma virus proved surprisingly deadly.
The rabbits developed skin nodules full of viruses. Then the infection spread to other organs, usually killing the animals within a few days. This cruel disease became known as myxomatosis.
The Brazilian scientists sent samples of the myxomavirus to Australia, where scientists tested it in labs for years to make sure it only posed a threat to rabbits and not other species. Some scientists even injected themselves with myxoma viruses.
After the virus was proven safe, the researchers sprayed it into a couple of pens to see what would happen. The rabbits died quickly, but not before mosquitoes bit them and spread the virus to others. Rabbits were soon dying hundreds of miles away, too.
Shortly after the introduction of Myxoma, Australian virologist Dr. Frank Fenner began a careful long-term study of his carnage. In the first six months alone, he estimated the virus killed 100 million rabbits. dr Fenner found in laboratory experiments that the myxomavirus killed 99.8 percent of the rabbits he infected, typically in less than two weeks.
But the myxomavirus did not wipe out Australian rabbits. In the 1950s, Dr. Fenner why: The myxoma virus became less deadly. In his experiments, the most common virus strains killed only 60 percent of the rabbits. And the rabbits that killed the tribes took longer to succumb.
This development fitted with ideas popular at the time. Many biologists believed that viruses and other parasites inevitably evolved more mildly – what became known as the law of diminishing virulence.
“Long-standing parasites have much less deleterious effects on the host through the evolutionary process than recently acquired ones,” zoologist Gordon Ball wrote in 1943.
According to the theory, newly acquired parasites were deadly because they had not yet adapted to their host. Keeping a host alive longer, it was thought, would give parasites more time to multiply and spread to new hosts.
The law of diminishing virulence seemed to explain why myxomaviruses became less deadly in Australia – and why they were harmless in Brazil. The viruses had evolved in South American cottontails for much longer, to the point where they no longer caused disease at all.
But evolutionary biologists have questioned the logic of the law in recent decades. Mildering may be the best strategy for some pathogens, but it’s not the only one. “There are forces that can push virulence in the other direction,” said Dr. Katzourakis.
dr Read decided to revisit the myxoma virus saga when he opened his lab at Penn State in 2008. “I knew it as a textbook case,” he said. “I started thinking, ‘Well, what happens next?'”
No one had systematically studied the myxoma virus after Dr. Fenner stopped doing it in the 1960s. (He had good reason to give it up, having moved on to help eradicate smallpox.)
dr Read arranged for the shipment of Dr. Fenner’s samples to Pennsylvania, and he and his colleagues also tracked down newer myxoma samples. The researchers sequenced the viruses’ DNA — something Dr. Fenner could not – and carried out infection studies on laboratory rabbits.
When they tested the virus lines prevalent in the 1950s, they found that they were less deadly than the original virus, supporting Dr. Fenner confirmed. And the death rate remained relatively low through the 1990s.
But then things changed.
Newer virus lines killed more lab rabbits. And they often did so in a new way: by turning off the animals’ immune systems. The rabbits’ normally harmless gut bacteria multiplied and caused deadly infections.
“It was really scary when we first saw that,” said Dr. Read.
Oddly enough, wild rabbits in Australia didn’t suffer the cruel fate of Dr. Read’s laboratory animals suffered. He and his colleagues suspect that the virus’ new adaptation was a reaction to the rabbits’ stronger immune system. Studies have shown that Australian rabbits received new mutations in genes involved in the first line of disease defenses known as innate immunity.
As the rabbits developed stronger innate immunity, Drs. Read and his colleagues, natural selection favored viruses that could overcome these defenses. This evolutionary arms race wiped out the advantage that wild rabbits had briefly enjoyed. But these viruses turned out to be even worse against rabbits that had not developed this resistance, like those in Dr. Read’s lab.
And the arms race continues. About a decade ago, a new lineage of myxomaviruses emerged in south-eastern Australia. This branch, called lineage C, develops much faster than the other lines.
Infection experiments suggest that new mutations allow lineage C to move better from host to host, according to the latest study by Dr. Read and his colleagues, which has not yet been published in a scientific journal. Many infected rabbits show a strange form of myxomatosis and develop massive swelling of the eyes and ears. It is precisely in these places that mosquitoes like to drink blood – and where the viruses may have a better chance of reaching a new host.
Virologists see some important lessons myxoma virus can offer as the world grapples with the Covid pandemic. Both diseases are influenced not only by the genetic make-up of the virus, but also by the defenses of its host.
As the pandemic enters its third year, people are better protected than ever thanks to the immunity that has developed from vaccination and infection.
But the coronavirus, like Myxoma, has not been on an inevitable path to leniency.
The Delta variant, which emerged in the United States last fall, was deadlier than the original version of the virus. Delta was replaced by Omicron, which caused less severe illness in the average person. However, virologists from the University of Tokyo have conducted experiments that suggest the Omicron variant is evolving into more dangerous forms.
“We don’t know what the next evolutionary step will be,” warned Dr. Katzourakis. “This chapter in the evolution of virulence has yet to be written.”