Evolution of Smallpox

Image from Babkin et al, 2006

Smallpox, Variola virus, is a complex double-stranded DNA virus that reproduces in the cytoplasm of its host cells. Substitutions in the genetic material of a virus are what lead to the evolution of new strains and species of viruses. By comparing isolated nucleotide sequences, scientists have been able to estimate the rate of substitutions within a specific sequence of genes. This estimate is known as the mutation rate and is assumed to be constant. By knowing the mutation rate, one can estimate the molecular clock and compose a phylogenetic tree for a living species. One evolutionary theory states that the phylogenetic tree of some viruses co-evolved parallel to the evolution of their host organisms and diverged at roughly the same time. However, in the case of DNA viruses such as Smallpox, the rate of accumulated mutations has been found to be much slower than once thought for viruses, though still significantly faster than mammalian mutation rates. It has been suggested that most likely the ancestor to a virus family had a much broader range of hosts, and their specialization to specific hosts occurred during a long period of co-evolution. Smallpox (Variola virus), is specialized to infect only human hosts and has no other vectors, but most likely diverged from an ancestor that infected a broad range of hosts (Babkin et al, 2006).

Smallpox comes from the Poxviridae family and genus Orthopoxvirus, which not only includes the human Variola virus, but also includes Monkeypox virus, Cowpox virus, and Vaccinia virus (the virus used to create smallpox vaccines). Using these DNA sequencing techniques, it has been estimated that the Poxviridae family diverged from a common ancestor about 500,000 years ago into two branches. One branch included the mammalian genus Orthopoxvirus, which diverged about 300,000 years ago. The modern Orthopoxvirus separated from a common ancestor about 14,000 years ago. Camelpox virus is most closely related to Variola virus and the two species diverged from a common zoonotic (meaning transferrable between different host animal species) ancestor about 6,000 years ago. This coincides with the appearance of large human settlements and the domestication of livestock (Babkin et al, 2006).

From an evolutionary perspective, a successful virus needs to balance its pathogenic effect on a host with the possibility of infecting another host. The Poxviridae family has been found to possess the largest number of mechanisms for overcoming the mammalian host’s innate immune defense systems (Shchelkunov, 2011). They show an amazing degree of coadaptation with their host species (Rubins et al, 2004). Most Orthopoxvirus species that can infect humans are zoonotic and have a very low mortality rate. Their virulence is much lower to increase the ability of the virus to spread between hosts in less densely populated areas, with the exception of Smallpox that evolved a much higher virulence to spread among densely populated human settlements.

After a massive vaccination program was launched by the World Health Organization, Smallpox was declared eradicated in 1980. However, many species of the Orthopoxvirus group are still endemic around the world. These species are highly zoonotic and though their mortality rate is significantly lower, sporadic cases of human outbreaks have been documented and studied around the world. One such instance included an outbreak of Vaccinia virus among dairy cattle that was observed to infect their human milkers on farms in Brazil in the year 2000. Though not fatal, the milkers developed lesions, fever, and symptoms similar to Smallpox infection, after coming into contact with lesions on the cow’s udders. This is one case of an ongoing epidemic of Zoonosis caused by the Vaccinia virus in southeast Brazil. This presents a really important public health concern, as the emergence of this Zoonosis 30 years after the end of smallpox vaccination points to a declined in Orthopoxvirus immunity. To top it off, health care professionals were unsure of how to diagnose and handle these infections, turning to methods of treatment that included excision of the lesions, which favors the spread of the virus (Trindade et al, 2007).

If you think these outbreaks must be isolated to rural underdeveloped areas in countries such as Brazil, think again.  In 2003, there were 72 confirmed or suspected cases of Monkeypox infection of humans in the United States. It is believed that the virus was first carried into the United States by an infected Gambian giant rat from Ghana, which subsequently infected a large shipment of 93 prairie dogs that were brought to Wisconsin, some of which were sold as pets. The infected patients contracted the virus from direct contact with the infected animals. In addition, quarantine of health care workers who were in direct contact with patients was also required to rule out human to human transmission (Cunha, 2004).

These cases of isolated outbreaks demonstrate that Orthopoxviruses are still a major endemic disease around the world, and because they are zoonotic, still pose a threat to human populations. Smallpox first evolved from an ancestor that was most likely a rodent-borne zoonotic disease before it specialized and became human specific. This begs the question, can we really consider Smallpox, Variola virus, eradicated?  Or will human populations see the rise of a new virulent species of Orthopoxvirus that is just as deadly, or even more so, than Smallpox in the future? With new phylogenetic data emerging and evidence of more evolving strains of orthopoxvirus, coupled with the declining immunity of human populations after the halt of Smallpox vaccination, and the dying knowledge about the disease family among the medical community, are we leaving ourselves open to a potentially deadly global threat?