The biggest rabbit hunt in human history: When the virus no longer evolves in the same way

It leaves us a lesson, when the Covid-19 pandemic is still not over.

It has been nearly 3 years since the Covid-19 pandemic began, and the mortality rate from SARS-CoV-2 virus infection has dropped to the lowest level since the beginning of the pandemic. This could be a sign that the virus is on the right track of its evolution, infecting more easily but also causing milder disease.

"There is a widespread notion that forces of nature will solve this pandemic for us," said evolutionary biologist Aris Katzourakis from the University of Oxford. As with many epidemics that have occurred in the past, the virus will either disappear spontaneously or spontaneously decrease in virulence and become a seasonal, flu-like endemic .

However, it is not without special cases. The evolution of virus strains often has something that we don't expect. For virologists, the best example of this is the story of Myxoma, a virus strain that became a terror to rabbits living in Australia in the 1950s.

The strange thing is that humans intentionally infect them with the Myxoma virus. The virulence of this virus strain can cause a fatality rate of up to 99.8%, and they have used it to control rabbits that are invading the entire continent of Australia.

100 million rabbits were killed by the Myxoma virus in just 6 months.

According to Andrew Read, an evolutionary biologist at Pennsylvania State University, Myxoma has killed hundreds of millions of rabbits , making it the most vertebrate-killing virus known to science . 'It was certainly the largest vertebrate carnage caused by the epidemic ,' Dr Read said.

The Australian rabbit slaughter continues to this day, even after 72 years, the Myxoma virus is still circulating in the rabbit population there. A familiar pattern is observed that, within a few years, the virus has decreased in virulence and mortality has decreased from 99.8% to about 50% in the years after the 1950s.

However, in their study, Dr. Read and colleagues found that Myxoma reversed course and increased their virulence back in the 1990s. And the latest study was published in June. It was also recently discovered that the Myxoma virus appears to be evolving to spread more rapidly in rabbit populations .

'It's still rolling out new tricks ,' says Dr Read.

The biggest rabbit hunt in human history

The story leads us back to 1895, an Australian farmer named Thomas Austin imported 24 rabbits in England, releasing them on his farm for hunting pleasure.

But what Austin did not anticipate was that the European rabbits when they arrived in Australia had no natural enemies. There are also not any pathogens that can infect and damage them.

As a result, from just 24 of the original Oryctolagus cuniculus rabbits , they multiplied into the millions, devouring vegetation, attacking sheep farms and threatening the lives of animals. other native wilds.

Thomas Austin, who is believed to have imported the Oryctolagus cuniculus rabbit into Australia and caused the rabbit epidemic.

In the early 1900s, researchers in Brazil came up with a solution for Australia. They discovered the Myxoma virus in a species of rabbit native to South America. Myxoma virus is spread by parasites such as mosquitoes and fleas, it does little harm to animals in general.

But when the scientists infected European rabbits with Myxoma in their lab, the virus displayed an astonishing super virulence. Infected rabbits will develop nodules on their skin, which are filled with virus.

When the virus infects the internal organs, they can kill the rabbit within a few days. This terrible disease is known as myxomatosis, or rabbit smallpox . Now, it could become a biological weapon to help Australia eradicate the rabbit population that is encroaching on the country.

And so the Brazilian scientists shipped some of their first samples of the Myxoma virus to Australia, where their scientists continued to spend years testing it in the lab.

The goal is to make sure the virus only poses a threat to rabbits, not other animals. Some Australian scientists even inject themselves with Myxoma virus to prove that this virus can not cause harm to humans.

In 1950, all safety tests for the Myxoma virus in the laboratory ended with positive results. The authorities were finally convinced, and the Australian National Industrial and Scientific Research Council then officially licensed the biological weapon to target the rabbit epidemic.

Myxoma virus under the electron microscope.

Scientists sprayed it at the mouths of rabbit holes in Wardang, an island south of Australia, to see what would happen next. The results were not unexpected, the rabbits died like stubble. Before long, the rabbit smallpox epidemic had spread to a radius of hundreds of miles, and the herds of rabbits living far from the site of the virus outbreak were not spared the cruel fate.

Dr Frank Fenner, an Australian virologist who has been following the rabbit eradication campaign since the early days, estimates that the Myxoma virus has killed at least 100 million rabbits in just six months. Rabbits after being infected with the virus will die in less than 2 weeks, the mortality rate is up to 99.8%. That means for every 500 rabbits infected with the virus, only 1 survives.

But the virus has entered the evolutionary rut

Thought Myxoma would be the end of rabbits in Australia, but no, evolution was once again on their side. After about a few years, the rabbits that had barely survived the smallpox epidemic finally repopulated.

They began to pass on their disease resistance genes to their progeny rabbits. Natural selection continuously finds rabbits that can withstand the Myxoma virus longer and have a higher chance of survival.

The virulence of the virus is also reduced. In the mid-1950s, Dr. Fenner discovered that the original strains of the Myxoma virus had reduced their fatality rate to only 60%. And when it becomes harder to kill rabbits, it turns to a strategy of increasing the infectivity.

Rabbits gather around a pool of water infested with Myxoma virus on Wardang Island.

This development was in line with popular ideas at the time, when many biologists believed that viruses and other parasites would inevitably evolve to gradually cause milder disease. This has even been codified into a principle called the law of virulence.

"Old parasites, over the course of their evolution, will gradually produce less harmful effects on the host than the more recent, emerging parasites," says zoologist Gordon Ball. wrote in 1943.

Theoretically, newly acquired parasites can quickly kill the host, because they have not yet adapted to the host. This is to their own detriment, because if the host dies too quickly, the parasites will not have enough time to reproduce and infect a new host. They eventually have to die with the host.

So keeping the host alive long enough is also part of the pathogen's own evolutionary strategy. This reduction in virulence also explains why the long-lived Myxoma virus in Brazil is almost harmless, while when it was first introduced into Australia, it killed rabbits like crazy.

Apparently in South America, the Myxoma had more time to evolve, getting to know their hosts better.

However, things don't always go according to plan. Evolutionary biologists have questioned the logic of the law of virulence in recent decades. Evolution to a milder pathogen may be the best strategy for some pathogens, but it is not the only strategy.

A breeding ground for the Myxoma virus infecting rabbits in Australia.

"There are pressures that can push the virulence of the pathogen in the other direction," said Dr. Katzourakis. In 2008, Dr. Read and his colleagues decided to roll back the Myxoma virus investigation at their lab at the University of Pennsylvania.

"I know this virus has been used as an example in a textbook ," he said. That is to say: Myxoma's decline in virulence has even been self-evident and no one doubts it anymore.

Dr. Fenner's research in the 1950s drove the final nail into the coffin lid to the law of reduction of toxicity. "But now, I'm starting to think, 'Well, what's going to happen next?" , Dr. Read said.

Flip the coffin lid

Fenner finished his last works on the Myxoma virus in the 1960s. And he had good reason to do so. The famous virologist's diary says it was around this time that he turned his attention to smallpox in humans.

Dr. Fenner was later appointed as an advisor, and eventually as Chairman of the Committee of the World Health Organization (WHO). It was he who led the world to eradicate smallpox in 1980.

But back to rabbit smallpox, with Dr. Fenner redirecting his research, the Myxoma viruses were of course left behind by him. So, in their new study, Dr. Read and his colleagues wanted to revisit Dr. Fenner's 1960s collection of specimens.

They sent them to the University of Pennsylvania for comparison and comparison with other, more recent strains of the Myxoma virus. The researchers also sequenced the virus's DNA - something Dr Fenner was unable to do - and performed infection studies on rabbits in the lab.

Dr. Frank Fenner, Australian virologist pioneered work on the study of Myxoma virus and rabbit smallpox.

The results showed that it was true that the strains that prevailed in the 1960s were less lethal to rabbits than the original strains. The results of gene sequencing further confirm Dr. Fenner's findings. The Myxoma virus was indeed attenuated during the period from 1960 to the 1990s. But then, everything changed.

Newer strains of the Myxoma virus killed more test rabbits. And more specifically, the viruses did it in a new way. They do not directly kill rabbits as before, but attack the host's immune system.

When rabbits' immune systems are weakened, they can no longer control the normal bacteria that live harmlessly in their intestines. They begin to emerge as pathogens, infecting and killing rabbits.

"The first time we saw it, it was really scary ," Dr Read said.

But oddly enough, he realized wild rabbits in Australia did not suffer the same gruesome fate as those in his laboratory. So, Dr. Read and colleagues suspect the evolution of the Myxoma virus is a response to stronger defenses in rabbits.

Studies have found that Australian rabbits have gained new mutations in genes related to the immune system, specifically the front lines that help them fight disease, known as the innate immune system .

The evolution of the Myxoma virus is a response to stronger defenses in rabbits.

As rabbits develop stronger innate immunity, natural selection puts pressure back on the Myxoma virus, forcing them to mutate and increase their virulence if they are to break through the rabbit's defenses. .

Both the host and the parasite are now thrust into an evolutionary arms race in which the original Myxoma strain briefly outpaced the wild rabbits. These viruses are even more aggressive towards rabbits that have not yet developed innate immunity, such as those in Dr. Read's lab.

And the story is not over, the arms race is still going on. About a decade ago, a new strain of Myxoma virus emerged in southeastern Australia. This branch, called Series C, is growing much faster than the other virus strains.

According to Dr. Read's latest research, the infection experiments he carried out showed that, with many new mutations, the Myxoma C Series virus is doing a better job of spreading from one host to another.

Many infected rabbits exhibit a strange form of rabbit smallpox. They develop large bumps on the eyes and ears. Those are exactly the places where mosquitoes like to suck blood - and where the virus has a better chance of reaching a new host through mosquito bites from an intermediate animal.

A rabbit died of rabbit smallpox, with virus-filled bumps in its ears.

But in the end, how can the story of rabbit smallpox help people? Virologists see some important lessons the Myxoma virus can teach us, as the world grapples with the Covid-19 pandemic.

As the pandemic drags on into its third year, all of us are more protected than ever thanks to acquired immunity from vaccinations or previous infections. But coronaviruses, like myxoma, don't just go in one direction to reduce virulence and cause milder illness.

For example, the Delta variant last year mutated to kill more people than the original version of SARS-CoV-2 in Wuhan. Now, Delta has been knocked out by Omicron, a variant that seems to cause less mild illness.

But virologists at the University of Tokyo have performed experiments that show the Omicron variant is evolving into the more dangerous forms originally. "We don't know what the next step in that evolution will be," warns Dr Katzourakis. If there is a textbook, "that chapter in the trajectory of virulent evolution has yet to be written" .