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Myxoma's viral leap into Iberian hares sheds light on how viruses swap genetic material

Iberian hare

For decades, there were reports of Iberian hares that had been found dead with lesions on their bodies that closely resembled that of myxoma virus-infected rabbits experiencing myxomatosis. To confirm that these hares were infected with a myxoma-like virus, tissue samples were collected and sequenced.

November 07, 2019

Viruses are all around us — they are present in most environments, lying in wait for the optimal host, and they even reside within our bodies, whether we know it or not. While hopping from species to species, these viruses can swap genetic material with each other and sometimes even with the host.

In fact, over the course of millions of years, viral DNA has been integrated into human chromosomes. It is estimated that about 100,000 pieces of viral DNA have merged with human DNA, making up nearly 10% of our entire genome.

That being said, little is known about the world of viruses, but recent efforts have been made to better understand how they work as they move from host to host.

In a paper recently published in Viruses (MDPI), an open-access, peer-reviewed journal, Arizona State University researchers Grant McFadden, professor and director of the Biodesign Center for Immunotherapy, Vaccines and Virotherapy; and Arvind Varsani, an associate professor in the Biodesign Center for Fundamental and Applied Microbiomics and associate faculty in the Biodesign Center for Mechanisms of Evolution; together with Ana Águeda-Pinto (visiting student from Universidade do Porto, Portugal) and her adviser Pedro Esteves, uncover how a recombinant myxoma virus allowed for a species leap from European rabbits to Iberian hares.

Our understanding of the myxoma virus first became a point of interest in the late 19th century, when European settlers introduced the European rabbit to Australia. When this invasive species began to multiply out of control in the 1950s, the settlers decided to release the myxoma virus into the feral rabbit population because it was known to cause myxomatosis — a lethal disease in rabbits. The introduction almost entirely decimated the population at first, but it later rebounded with rabbits that were more resistant to the lethal effects of the virus.

It was later discovered that this same strategy was not effective for rabbits inhabiting the Americas, as they did not develop myxomatosis. Upon further investigation, another surprising characteristic of the virus came to light. When cancerous human cells were exposed to myxoma, the virus killed them, while leaving healthy cells unaffected. This kickstarted a flurry of research into how the myxoma virus works, including how it recombines and what threat or advantage it could pose, were it to leap between species.

The myxoma virus is part of the of poxvirus family and is thus a double-stranded DNA virus that grows in the cytoplasm of an infected cell, as opposed to the nucleus. These versions of viruses are unique in that they encode for the enzymes needed to express their own genes. In this way, they are more autonomous because they don’t need to hijack as many materials from the host as other viruses often do.

“One of the things we know is that when two poxviruses are in a cell together, they are really good at exchanging information, so when they recombine with each other, the new virus that comes out is generally viable and ready to leap out on its own. Whether it will or will not depends on circumstances,” McFadden said.

These recombinant versions may have the genes necessary to thrive in a new host; however, although viruses are constantly exchanging their DNA segments, creating a recombinant virus with the ability to hop to a new species is extremely rare.

“Viruses are trying to leap species all the time, but they are mostly failing over and over again,” McFadden said. “Every now and then, a success happens — the virus pops up in a host in which it didn’t exist before.”

This was the case outlined in the paper. For decades, there were reports of Iberian hares that had been found dead with lesions on their bodies that closely resembled that of myxoma virus-infected rabbits experiencing myxomatosis. To confirm that these hares were infected with a myxoma-like virus, tissue samples were collected and sequenced. The DNA sequence revealed a new virus with a large conserved region derived from myxoma virus along with a recombinant region that had never been observed before.

“We didn’t know until we sequenced it, and lo and behold, it was clearly a recombinant poxvirus that is mostly myxoma but with a tiny chunk of information from another poxvirus,” McFadden said.

One of the few recombination events that yielded the right conditions for a species leap includes the initial emergence of myxoma in rabbits.

“Myxoma originally existed in the Brazilian rainforest in an animal called a tapeti,” McFadden said. “In the tapeti, it’s not a pathogen, but if a mosquito comes along, bites the tapeti, and then goes and bites a European rabbit and transmits the virus, it’s good to go to cause myxomatosis.”

This brings to light the wide variety of avenues the myxoma virus may have taken in leaping to the Iberian hare species.

“There’s all kind of answers: sometimes they just need an opportunity to leap, sometimes you just have to mutate the parent virus and sometimes recombination between two viruses can give new progeny viruses that can leap.”

The researchers theorize that the recombination events could have happened within rabbits or within an intermediary species, such as an ungulate (a hoofed animal). As to how the parent virus or the resulting recombinant myxoma virus was transmitted, not much is known.

The parent virus (with which myxoma virus recombined) could have been delivered to rabbits or an intermediary species via contact with virus-induced lesions or via horse flies. Other theories suggest that the parent virus could have been acquired from fecal matter, from injuries caused during fights, or even something as far-fetched as inheriting the virus from the talons of a bird.

“The virus doesn’t care how any of it happens. As soon as it comes into contact, bingo, the viruses begin to swap genes,” McFadden said. “It’s worthy of an Agatha Christie plot — it could have been the cook with the candlestick in the basement."

The researchers believe that with time, these viral leaps will increase in frequency as climate change progresses. Many species will have move to new environments with more livable temperatures and ample resources, causing new viral interactions.

“Almost for sure, viruses will get a broader range in which to query hosts with climate change. All living organisms are being sniffed by viruses all the time. When you start changing environments, it’s the lottery for the viral world,” McFadden said. “Viruses only care about whether or not they can survive.”

“If you bring two animals or species that rarely come into contact and put them in a confined space, the propensity of them interacting directly or indirectly via vector is much more likely — the potential for a species leap increases dramatically,” Varsani added.

And although new viruses may pose an immediate threat to species, including humans, not all viruses will end with the host dying. The goal of every living thing is to survive and replicate — if a virus kills its host, it can no longer do that. 

“Virulence is more often than not an accident; some need pathogenesis to survive but it’s rare,” McFadden said. “When a new virus finds a new host, if it’s really lethal, mother nature tends to play this ping pong between the host and the virus to make it less lethal. It’s not good for the spread of the virus to kill all the hosts.”

As was the case for the original rabbit populations, which were nearly decimated by myxomatosis, the lethality of a virus tends to decline over generations as those individuals that have some sort of immunity to the disease will survive and pass on that resistance to their offspring.

“The lethal viruses wipe out a large population but there are certain individuals having an arms race with the virus where they have some immunity,” Varsani said.

The researchers don’t plan to stop their research on the recombinant virus here. They want to track which genes allowed for the species leap via fluorescent proteins and establish in a controlled experimental environment whether the virus they isolated and grew from the tissue samples can cause myxomatosis in the hares.

Could this virus also be useful for cancer virotherapies? The question has yet to be explored.  

“For all I know, this new construct could kill human cancer cells better than the parental viral construct,” McFadden said. “There is no obvious connection to virotherapy, but there is also no obvious non-connection either.”

Understanding how viruses recombine and leap to new species could provide universal knowledge for the field of virology.

“I think the main thing is to remind people that it’s easy to convince people to study things that have already popped up in humans like HIV, but it is harder to convince people to study how mother nature gets to that product,” McFadden said. “Convincing the general public to fund that is a much harder feat, but I would argue it’s every bit as important.”

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