The vaccinia virus that jumped from rabbits to hares

The smallpox viruses are back and it’s no surprise. When the World Health Organization announced the eradication of smallpox more than 40 years ago, they also stopped vaccinating against this deadly infectious disease. As a result, much of the world’s population now lacks protection from smallpox or the wide range of other smallpox viruses, including monkeypox, deer pox, rabbit pox, and other zoonotic diseases. Researchers have long predicted that stopping smallpox vaccinations would allow the emergence of new virulent strains of smallpox and other poxviruses. Increasing reports of monkeypox infections in humans have confirmed these concerns. While the origins of monkeypox are not clear, the common traits of a newly discovered strain have allowed this virus to spread more quickly from the native regions of West Africa. At this stage, these infections are unlikely to lead to a major pandemic, but this will not always be the case.

As viruses jump from one host to another, different molecular interactions affect the genes of both 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 else to go. At the same time, animal species will naturally develop mechanisms over time to reduce fatalities and attenuate the severity of symptoms associated with viral infection. Through natural selection, individuals with certain genes have a greater chance of surviving an infection. This arms race between host and virus allows viruses to remain in animal populations for several generations.

Sufficient changes in the virus genome can allow a pathogen to cross over into and infect other animal populations. Referred to as a spillover event, exposure to newly mutated viruses can have significant consequences as the virus continues to replicate and mutate into new hosts. When this happens, the crucial question is whether the new virus 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. The myxoma virus initially discovered in South American rabbits was deliberately released in Australia in 1950 to control the population of European rabbits. Since then, scientists have monitored not only how the rabbit population has changed, but also variations in the viral genome.

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

How can a virus become 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 quickly infects and kills hosts has a much shorter infectious period, limiting the window to infect others.

However, decreased virulence does not explain why different populations of rabbits experience different mortality rates when exposed to the same myxoma virus. For example, within 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 the rabbits in the same area. These rabbits appeared to have developed a genetic resistance to the myxoma virus, with innate and adaptive immunity being able to control the severity of the 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 go away completely.

In this arms race, changes in 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 enhance infection. These proteins manipulate and suppress the host’s immune system to prolong the infectious period. A study at Pennsylvania State University found that increased infectivity between different animal populations may be linked to single mutations, or multiple mutations over time, that facilitate the expression of novel host range factors. Therefore, despite how many hosts evolve to resist viral infection, the rabbit pox virus continues to find new ways to circumvent these mechanisms.

Because the host range factors of a virus are specific to the type of hosts they infect, other species are usually unaffected by new viral strains. Occasionally, key mutations can allow poxviruses to cross the species barrier. When hundreds of hares from the Iberian Peninsula suddenly died from rabbit pox-like infections in the fall of 2018, such an event was suspected to have occurred.

Researchers from the University of Arizona recently published a report which identified the key mutation that caused the rabbit pox virus to kill in Iberian hares. These hares have been living alongside European rabbits since the 1990s, but they have only recently been susceptible to a new strain of the rabbit pox myxoma virus. Although rabbits and hares look alike, they are completely different species. Physical, behavioral and lifestyle differences between rabbits and hares are mediated by genetic evolutionary variations of their common ancestor. As a result, these two species are not equally susceptible to the same diseases. When smallpox viruses jump from one species to another, it can have profound effects not only on animal health but also on humans.

Understanding how this virus can cross from one species to another can provide insight into preventing further viral strains that could target humans. Now more than ever, it’s critical to identify overflow events as they occur and isolate viruses before they have a chance to spread. In the next part of this series, we’ll examine the findings of this study to determine how this smallpox virus jumped from one species to another.

The message here is that smallpox viruses, like other viruses, are not stable. They adapt and mutate with their environment. The SARS-CoV-2 virus was no exception. This virus thrives in bats that have evolved genetically to avoid getting sick. However, a recombination change in the viral genome made the SARS-CoV-2 virus more lethal and eventually spread to humans. Climate change and increasing globalization allow viruses to mutate and spread at unprecedented rates.

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

(1) Restore smallpox vaccinations to address emerging poxvirus strains.

(2) More 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 when they occur.

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