Smallpox viruses are back, which is not surprising. When the World Health Organization declared smallpox eradicated more than forty years ago, it also halted vaccination against this deadly contagious disease. Consequently, much of the world’s population now has no protection against smallpox or a wide range of other smallpox viruses, including monkeypox, elk pox, rabbit pox, and other animal diseases. Researchers have long speculated that stopping smallpox vaccination would enable the emergence of new virulent strains of smallpox and other smallpox viruses. Increasing reports of monkeypox infections in humans have confirmed these concerns. Although the origin of monkeypox is not clear, typical characteristics in a newly discovered strain allowed this virus to spread more rapidly than in the original regions of West Africa. At this point, this infection is unlikely to result in a major pandemic, but that will not always be the case.
When 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 viral pathogens and their hosts. The goal of any virus is to infect as many hosts as possible, but killing that much of the population means the virus has nowhere else to jump. At the same time, animal species over time will naturally develop mechanisms to reduce mortality and attenuate the severity of symptoms associated with viral infection. Through natural selection, individuals with certain genes are more likely to survive infection. The arms race of the host virus is what allows viruses to be contained within animal populations for multiple generations.
Sufficient changes in the virus genome can enable the pathogen to cross and infect other animal populations. Referred to as an indirect event, exposure to newly mutated viruses can have severe consequences as the virus replicates and mutates in new hosts. When this happens, the important 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 co-evolution of myxoma virus in European rabbits. The myxomavirus that causes rabbit pox was initially discovered in South American rabbits, and was deliberately released in Australia to control the European rabbit population in the 1950’s. Since then, scientists have not only tracked how rabbit numbers have changed but also differences in the viral genome.
To their surprise, the myxoma virus that originally had a mortality rate of almost 100% was replaced by less lethal strains that killed only 70-85% of its hosts. The mortality rate for some strains of the myxoma virus has reportedly been less than 50%.
How can the virus become less dangerous the more it spreads? Australian researcher Frank Viner and his colleagues were the first to show that natural selection favors less virulent viruses. The virus is so virulent that infecting and killing hosts quickly, it has a much shorter infectious period, which limits its window of infecting others.
However, the lower virulence does not explain why different groups of rabbits experience varied mortality rates when exposed to the same myxovirus. For example, within seven years, the myxoma strain that had a 90% mortality rate in rabbits living in Lake Orana killed only 26% of rabbits in the same area. These rabbits appear to have developed genetic resistance to myxomavirus, in which innate and adaptive immunity can control the severity of infection even when responding to the most virulent viral strains. While a strong immune response keeps the animal alive, a particularly dangerous viral strain can spread further during the period of increased infection. This is why the deadliest viruses do not completely disappear.
In this arms race, changes in the viral genome also enable new strains to suppress the immune response of the increasingly resistant host. Like other poxviruses, myxovirus encodes several proteins called host domain factors that promote infection. These proteins manipulate and suppress the host’s immune system to prolong the infection period. One study from Penn State University found that increased infection between different animal groups may be associated with single mutations, or multiple mutations over time, that facilitate the expression of new host domain factors. Therefore, despite the extent to which hosts have evolved to resist viral infection, rabbit pox virus continues to find new ways to bypass these mechanisms.
Because virus host range factors are specific to the type of host it infects, other species are usually not affected by new viral strains. Occasionally, major mutations may enable poxviruses to cross the species barrier. When hundreds of wild rabbits from the Iberian Peninsula died suddenly of a rabbit pox-like infection in the fall of 2018, such an event was suspected.
Researchers at the University of Arizona recently published a report that identified the key mutation that allowed rabbit pox virus to cross lethally into Iberian rabbits. These rabbits have lived alongside European rabbits since the 1990s, but only recently were they exposed to a new strain of rabbit pox myxomavirus. Although rabbits and hares are similar, they are two completely different species. The physical, behavioral, and lifestyle differences between rabbits and rabbits are mediated by genetic evolutionary differences from their common ancestor. As a result, these two species are not prone to developing the same diseases. When smallpox viruses pass from one species to another, there can be profound effects not only on animal health but also on human health.
Understanding how this virus is transmitted from one species to another may provide insight into preventing further strains of the virus that could target humans. It is now more important than ever to identify spillovers 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 the smallpox virus is transmitted from one species to another.
The take-home message here is that smallpox viruses, like other viruses, are not stable. They adapt and transform with their environment. SARS-CoV-2 was no exception. This virus spread in bats that have genetically evolved to avoid contracting the disease. Changing the structure in the viral genome, however, allowed SARS-CoV-2 to become more lethal, and eventually spread to humans. Climate change and increasing globalization have enabled viruses to mutate and spread at unprecedented rates.
There are steps we can take now to delay the next major pandemic:
(1) Reintroduction of smallpox vaccines to target emerging smallpox virus strains.
(2) Increase testing of antiviral therapies by supporting academic and pharmacological research.
(3) Development of a multidimensional therapeutic approach that includes vaccinations and antiviral drugs not only to prevent infection but also to respond effectively to outbreaks when they occur.