Hop to it: Researchers evaluate rabbits’ evolved resistance to myxoma virus

It's common knowledge that rabbit populations are not easily controlled — they reproduce swiftly, and as a result, they have a severe impact on their environment, as when European settlers introduced the wild European rabbit to Australia in the late 19th century. In an attempt to reduce the population size that had grown to almost a billion rabbits by 1950, Australian scientists released the myxoma virus — a virus known to be deadly to rabbits at the time — to the rabbit population, and eventually did the same for populations in France and the U.K. However, after some time, fatality rates lessened in all three countries, and the rabbit populations rebounded but were now genetically more resistant to the virus.

Regarded as “one of the greatest natural experiments in evolution,” researchers naturally wanted to learn more, so they tackled the genetic basis of the newly resistant rabbit adaptation to this virus.

Partnering with the University of Cambridge and several other research institutes, researchers at the Biodesign Institute at Arizona State University, as part of Grant McFadden’s Center for Immunotherapy, Vaccines and Virotherapy, validated the role of specific rabbit genes in contributing to this acquired resistance in research published in Science magazine.

McFadden’s lab has many decades of expertise in the myxoma virus, studying subjects ranging from the virus’s replication in hosts to its potential use in treating cancer. For this project, they were tasked with determining whether certain rabbit genes that had changed in the 70 years of exposure to the virus were responsible for the rabbits’ acquired resistance to the virus.

“There are rabbits in each population that evolved at the same time but independently of each other,” said McFadden, a professor in the School of Life Sciences and director of the Center for Immunotherapy, Vaccines and Virotherapy. “The idea was to sequence examples of many rabbit genomes of all three places and see what they have in common, and that’s what led to this study. We came up with half a dozen gene variations in common — our job was to determine whether these variants of genes affected that virus in a lab setting.”

While the rabbits that were resistant to the virus survived and thus were selected for, the less pathogenic viruses were also selected for among the viral populations. This coupled with the fact that the same trend was seen in three geographically distinct regions of the world, serve as a concrete example of co-evolutionary forces that operate between viruses and their hosts, and being able to determine the genetic basis of this adaptation only furthers our knowledge of parallel adaptation.

“The host and the virus began to do a genetic dance with each other that was started over 70 years ago. For decades after that, no one knew what that genetic dance was, but now we have learned something new from the genomes of the surviving rabbits,” McFadden added.   

The researchers in the U.K. were largely responsible for utilizing modern sequencing technology to sequence the rabbit genomes in the populations now and compare them to genomes from past generations, while McFadden and his lab were responsible for determining whether the genes that emerged in all three rabbit populations were correlated to antiviral effects by testing the virus in cell culture. Ana Lemos de Matos and Masmudur Rahman, a postdoc and an associate research professor in McFadden’s lab, respectively, were responsible for testing the effect of these genes on the myxoma virus. 

By doing so, the researchers were able to validate the role of these genes in viral replication and indicated that selection for a more effective interferon response as part of the innate immune response to viral infection in rabbit populations was at play.

McFadden and his lab believe that one of the main takeaways from this study was to prove that co-evolution happens and can occur quickly after new virus-host interactions emerge.

“This is probably one of the best examples of co-evolution that we know of, where the virus is evolving, and the host is evolving, and they are evolving in concert with each other,” McFadden said. “This is a wonderful example of pure-curiosity research, and there may be implications down the line, but in terms of co-evolution, I can’t think of a better example on the planet.”