Do you think all viruses fade over time? Not this bunny killer.

As the global Covid death rate has fallen to its lowest level since the first weeks of the pandemic in 2020, it may be tempting to conclude that the coronavirus is getting irreversibly milder. This notion matches a widespread belief that all viruses start out nasty and inevitably evolve to become milder over time.

“There’s been this mainstream narrative that natural forces are going to solve this pandemic for us,” said Aris Katzourakis, an evolutionary biologist at the University of Oxford.

But such a natural law does not exist. 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 ravaged 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, the myxoma virus became less lethal to rabbits, but Dr Read and his colleagues discovered that it had reversed in the 1990s. And the researchers’ latest study, published this month- ci, revealed that the virus appeared to be evolving to spread even faster from rabbit to rabbit.

“There’s still new stuff,” he said.

Scientists intentionally introduced the myxoma virus to Australia in hopes of eliminating the country’s invasive rabbit population. In 1859, a farmer named Thomas Austin imported two dozen rabbits from England so he could hunt them on his farm in Victoria. Without natural predators or pathogens to hold them back, they multiplied into the millions, eating enough vegetation to threaten native wildlife and sheep farms across the continent.

In the early 1900s, Brazilian researchers proposed a solution to Australia. They had discovered the myxoma virus in a species of cottontail rabbit native to South America. The virus, spread by mosquitoes and fleas, caused little harm to animals. But when scientists infected European rabbits in their lab, the myxoma virus proved surprisingly deadly.

The rabbits developed virus-filled skin nodules. Then the infection spread to other organs, usually killing the animals within days. This horrible disease is known as myxomatosis.

Brazilian scientists shipped samples of the myxoma virus to Australia, where scientists spent years testing it in the lab to make sure it only posed a threat to rabbits and not other species. A few scientists have even injected themselves with myxoma viruses.

Once the virus was found to be safe, researchers sprayed it in a few burrows to see what would happen. The rabbits died quickly, but not before mosquitoes bit them and transmitted the virus to others. Soon rabbits hundreds of miles away were also dying.

Shortly after myxoma was introduced, 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 determined in laboratory experiments that the myxoma virus killed 99.8% of the rabbits it infected, usually within two weeks.

Yet the myxoma virus did not eradicate Australian rabbits. During the 1950s, Dr. Fenner discovered why: the myxoma virus became less deadly. In his experiments, the most common strains of the virus killed as few as 60% of rabbits. And the rabbits that the stumps killed took longer to succumb.

This development corresponded to the ideas received at the time. Many biologists believed that viruses and other parasites inevitably evolved to become softer – which became the law of declining virulence.

“Parasites of long standing, by the process of evolution, have much less harmful effect on the host than those recently acquired,” wrote zoologist Gordon Ball in 1943.

According to the theory, the newly acquired parasites were deadly because they had not yet adapted to their hosts. Keeping a host alive longer, it was thought, gave parasites more time to multiply and spread to new hosts.

The law of decreasing virulence seemed to explain why myxoma viruses became less deadly in Australia – and why they were harmless in Brazil. Viruses had been evolving in cottontail rabbits in South America for much longer, to the point that they did not cause any disease.

But evolutionary biologists have come to question the logic of the law in recent decades. Going softer may be the best strategy for some pathogens, but it’s not the only one. “There are forces that can push virulence the other way,” Dr. Katzourakis said.

Dr. Read decided to revisit the myxoma virus saga when he opened his lab at Penn State in 2008. “I knew it like a textbook case,” he said. “I started thinking, ‘Well, what happens next?'”

No one had systematically studied the myxoma virus after Dr. Fenner quit in the 1960s. (He had good reason to give it up, as he had left to help eradicate smallpox.)

Dr. Read arranged for Dr. Fenner’s samples to be shipped to Pennsylvania, and he and his colleagues also tracked down more recent myxoma samples. The researchers sequenced the viruses’ DNA – which Dr. Fenner was unable to do – and conducted infection studies in lab rabbits.

When they tested the viral lineages that had been dominant in the 1950s, they found that they were less lethal than the original virus, confirming Dr. Fenner’s findings. And the death rate remained relatively low in the 1990s.

But then things changed.

New virus lines killed more lab rabbits. And they often did it in a new way: by shutting down the animals’ immune systems. Rabbits’ normally harmless gut bacteria multiply and cause life-threatening infections.

“It was really scary when we first saw this,” Dr Read said.

Strangely, the wild rabbits of Australia did not suffer the gruesome fate of Dr Read’s laboratory animals. He and his colleagues suspect that the viruses’ new adaptation was a response to stronger defenses in rabbits. Studies have revealed that Australian rabbits have acquired new mutations in genes involved in the first line of defense against disease, known as innate immunity.

As rabbits developed stronger innate immunity, Dr Read and his colleagues suspect that natural selection, in turn, favored viruses that were able to overcome this defence. This evolutionary arms race erased the advantage the wild rabbits had briefly enjoyed. But these viruses proved even worse against rabbits that hadn’t developed this resistance, like those in Dr. Read’s lab.

And the arms race continues. About a decade ago, a new lineage of myxoma virus emerged in southeastern Australia. This branch, called Lineage C, evolves much faster than the other lines.

Infection experiments suggest new mutations allow Lineage C to move better between hosts, according to the latest study by Dr Read and colleagues, which has yet to be published in a journal. scientific. Many infected rabbits show a strange form of myxomatosis, developing massive swellings in the eyes and ears. It is precisely these places where mosquitoes like to drink blood – and where viruses can have a better chance of reaching a new host.

Virologists see some important lessons the 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 continues into its third year, people are more protected than ever thanks to the immunity that has developed from vaccinations and infections.

But the coronavirus, like myxoma, has not been on an inevitable path to mildness.

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 for the average person. But virologists at the University of Tokyo have conducted experiments suggesting that the Omicron variant evolves into more dangerous forms.

“We don’t know what the next stage of evolution will be,” warned Dr. Katzourakis. “This chapter of the evolutionary trajectory of virulence has yet to be written.”

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