The Vaccinia Virus That Hopped From Rabbits to Hares

(Posted on Wednesday, June 1, 2022)

Poxviruses are back, and it is no surprise. When the World Health Organization announced the eradication of smallpox over forty years ago, they also halted vaccinations against this lethal infectious disease. Consequently, much of the world population now has no protection against smallpox or the wide array of other poxviruses, including monkeypox, deerpox, rabbitpox and other zoonotic diseases. Researchers have long predicted that halting smallpox vaccinations would enable the emergence of new virulent strains of smallpox and other poxviruses. Increasing reports of monkeypox infections in humans has confirmed these concerns. Although the origin of monkeypox is not clear, usual properties in a newly detected strain has allowed this virus to spread more rapidly from indigenous regions of western Africa. At this stage, it is unlikely that these infections will lead to a major pandemic, but this will not always be the case.

As viruses jump from one host to another, different molecular interactions influence the genes of both the host and virus. This fuels an arms race between a viral pathogen and its hosts. The goal of any virus is to infect as many hosts as possible but killing to much of the population would mean the virus has nowhere else to jump. Simultaneously, animal species over time will naturally develop mechanisms to reduce fatalities and weaken the severity of symptoms associated with viral infection. Through natural selection, individuals with certain genes are more likely to survive infection. This host-virus arms race is what allows viruses to be contained within animal populations for multiple generations.

Enough changes to the virus’s genome can enable a pathogen to cross to and infect other animal populations. Referred to as a spillover event, exposure to newly mutated viruses can have significant consequences as the virus further replicates and mutates in new hosts. When this happens, the critical question is whether the new viral strain is more or less virulent than the original virus.

One of the most documented examples of this is the coevolution of the myxoma virus in European Rabbits. Initially detected in South American rabbits, the myxoma virus that causes rabbitpox was intentionally released in Australia to control the population of European rabbits in 1950. Since then, scientists have not only tracked how the rabbit population has changed but also variations in the viral genome.

To their surprise, the myxoma virus that originally had a nearly 100% fatality rate was replaced by less fatal strains that only killed 70-85% of its hosts. Some strains of the myxoma virus reportedly had less than a 50% fatality rate.

How is it possible that a virus becomes less dangerous the more it spreads? Australian researcher Frank Fenner and his colleagues were the first to show that natural selection favored less virulent viruses. A highly virulent virus that rapidly infects and kills hosts has a much shorter infectious period, limiting its window to infect others.

Decreased virulence, however, does not explain why different populations of rabbits experience varied fatality rates when exposed to the same myxoma virus. For example, within a seven-year period, a myxoma strain that once had a 90% fatality rate in rabbits living in Lake Urana only killed 26% of rabbits in the same area. These rabbits appeared to have developed a genetic resistance to the myxoma virus, in which innate and adaptive immunity could control the severity of infection even in response to the most virulent viral strains. While a strong immune response works to keep the animal alive, a particularly dangerous viral strain can spread more during the increased infectious period. This is why more virulent viruses never completely disappear.

In this arms race, changes to the viral genome also enables new strains to suppress the increasingly resistant host immune response. Like other poxviruses, the myxoma virus encodes several proteins called host range factors that enhance infection. These proteins manipulate and suppress the host’s immune system to prolong the infectious period. One study from Pennsylvania State University found that increased infectability between different animal populations may be linked to single mutations, or multiple mutations over time, that facilitate the expression of new host range factors. Therefore, despite how much hosts evolve to resist viral infection, the rabbitpox virus continues to find new ways to bypass these mechanisms.

Since a virus’s host range factors are specific to the type of hosts they infect, other species are usually not affected by new viral strains. Occasionally, key mutations may enable poxviruses to cross the species barrier. When hundreds of hares from the Iberian Peninsula suddenly died from rabbitpox-like infections in fall 2018, it was suspected that such an event had occurred.

Researchers at Arizona University recently published a report that identified the key mutation that allowed the rabbitpox virus to lethally cross into Iberian hares. These hares have lived alongside European rabbits since the 1990’s, but they only recently have been susceptible to a novel strain of the rabbitpox myxoma virus. Although rabbits and hares look alike, they are entirely different species. Physical, behavioral and lifestyle differences between rabbits and hares are mediated by genetic evolutionary variations from their common ancestor. As a result, these two species are not equally susceptible to the same diseases. When poxviruses jump from one species to another, there may be profound implications for not only animal but also human health.

Understanding how this virus could cross from one species to another may provide insight to preventing further viral strains that could target humans. It is critical now more than ever to identify spillover events as they occur and isolate viruses before they have a chance to spread. In the next part of this series, we will examine the findings from this study to determine how this poxvirus hopped from one species to another.

The take-home message here is that poxviruses, like other viruses, are not stable. They adapt and mutate with their environment. The SARS-CoV-2 virus was no exception. This virus thrived in bats that have genetically evolved to avoid getting sick. A recombination change in the viral genome, however, allowed the SARS-CoV-2 virus to become more lethal, eventually spreading to humans. Climate change and increased globalization has enabled viruses to mutate and spread at unprecedented rates.

There are steps that we can take now to delay the next major pandemic:

(1)   Reinstate smallpox vaccinations to target emerging poxvirus strains.

(2)  Increase testing for antiviral treatments by supporting academic and pharmacological research.

(3)  Develop a multidimensional therapeutic approach that includes vaccinations and antivirals to not only prevent infections but also effectively respond to outbreaks as they occur.

Read the full article on Forbes.