The vaccinia virus that jumped from rabbit to hare

Poxviruses are back, and it’s no surprise. When the World Health Organization announced the eradication of smallpox over forty years ago, it also halted vaccinations against this deadly infectious disease. As a result, much of the world’s population now has no protection against smallpox or the wide range of other poxviruses, including monkeypox, deerpox, rabbitpox, and other zoonotic diseases. Researchers have long predicted that stopping smallpox vaccinations would allow new virulent strains of smallpox and other poxviruses to emerge. Increasing reports of monkeypox infections in humans have confirmed these concerns. Although the origin of monkeypox is unclear, the usual properties of a newly detected strain allowed this virus to spread faster from native regions of West Africa. At this point, these infections are unlikely to lead to a major pandemic, but that won’t always be the case.

When viruses move from one host to another, different molecular interactions influence the genes of the host and the 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 a large portion of the population would mean the virus has nowhere to jump. Simultaneously, animal species will naturally develop mechanisms over time to reduce deaths and weaken the severity of symptoms associated with viral infection. Through natural selection, individuals carrying certain genes are more likely to survive infection. This host-virus arms race is what allows viruses to be contained in animal populations for multiple generations.

Sufficient changes to the virus genome can allow a pathogen to cross over and infect other animal populations. Considered a spillover event, exposure to newly mutated viruses can have significant consequences as the virus replicates and mutates further in new hosts. When this happens, the crucial 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 myxoma virus in European rabbits. Originally detected in South American rabbits, the myxoma virus that causes rabbit pox was intentionally released in Australia to control the population of European rabbits in 1950. Since then, scientists have not only tracked the population of rabbits, but also the variations of the viral genome.

To their surprise, the myxoma virus which originally had a mortality rate of almost 100% was replaced by less lethal strains which only killed 70-85% of its hosts. Some strains of the myxoma virus are said to have had a mortality rate of less than 50%.

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

However, the decrease in virulence does not explain why different rabbit populations experience varying mortality rates when exposed to the same myxoma virus. For example, over a seven-year period, a strain of myxoma that once had a 90% mortality rate in rabbits living in Lake Urana killed only 26% of rabbits in the same area. These rabbits appeared to have developed 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 virus strains. While a strong immune response helps keep the animal alive, a particularly dangerous virus strain can spread further during the heightened infectious period. This is why more virulent viruses never completely disappear.

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

Since a virus’s host-range factors are specific to the type of hosts it infects, other species are generally unaffected by new virus strains. Occasionally, key mutations can allow poxviruses to cross the species barrier. When hundreds of hares on the Iberian Peninsula suddenly died of rabbitpox-like infections in the fall of 2018, it was suspected that such an event had occurred.

Researchers at the University of Arizona recently published a report who identified the key mutation that allowed the rabbitpox virus to lethally cross Iberian hares. These hares have lived alongside European rabbits since the 1990s, but only recently have they become susceptible to a new strain of rabbitpox myxoma virus. Although rabbits and hares look alike, they are totally different species. The 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 can be profound implications not only for animal health but also for human health.

Understanding how this virus could jump from one species to another can provide insight into preventing new viral strains that could target humans. It is more critical 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 results of this study to determine how this poxvirus jumped between species.

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 evolved genetically to avoid getting sick. A recombination change in the viral genome, however, allowed the SARS-CoV-2 virus to become more deadly, eventually spreading to humans. Climate change and increased globalization have allowed viruses to mutate and spread at unprecedented rates.

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

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

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

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

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