Unlike diseases that require specific behaviors or cultural customs to spread, Smallpox is a proximity based disease that must rely on direct contact of a person with the bodily fluids of an infected person. It is estimated to have diverged from its last common ancestor about 6,000 years ago, coinciding with the appearance of large human settlements and the domestication of livestock (Babkin et al, 2006). With the rise of agriculture and dense human populations, rodents carrying Smallpox’s last common ancestor were attracted to the stores of grains and initiated the evolution of a specialized human specific virus (Pearce-Duvet 2006). The density of human settlements allowed for this more virulent species of host specific virus to spread effectively among populations. By the mid-twentieth century, Smallpox was largely eradicated from modern civilizations due to better health care initiatives and vaccination availability. It continued to proliferate within the third world, primarily sub-Saharan Africa, South America, Southeast Asia, and India, because of lack of initiatives and access to modern health care. Extended vaccination would not occur in these areas until 1967 (CDC Smallpox zones, 1955).
Wednesday, May 4, 2011
Evolution of Smallpox
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| 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?
History of Smallpox
Smallpox is believed to have existed within human populations since 10,000 BCE. There is some debate on exactly when it came about, however it is generally agreed upon that Smallpox first appeared around the same time as agricultural communities. Modern genetic studies of the Variola virus continue to alter the timeline. The first archaeological evidence showing Smallpox comes from mummies dating back the 18th Dynasty of Egypt, specifically Ramses V (1157 BCE). Upon his discovery in 1898, scientists had speculated about what may have caused his death. Because he was mummified in the traditional fashion, much of his body remained relatively preserved. The token signs of Smallpox (rash, blisters, etc.) are said to be present on his mummified skin. Smallpox itself is believed to have originated in Africa and Asia. The two different strains of Smallpox, V. major and V. minor, originate from West Africa and India, respectively. Historical records and medical depictions show evidence of Smallpox in China (1122 BCE) and India as early as 1500 BCE. (Li, Carroll, Gardner, Walsh, Vitalis, Damon. 2007)
How the disease ended up in Europe is much less clear. Neither the Old Testament nor the New Testament describe anything like Smallpox. The same is true for early Greek and Roman literature. Some scholars speculate that the Antonine Plague of 165-180 CE may have been caused by Smallpox (Murphy, 2005), while others say that the Arab armies brought the disease to Southwest Europe during the Islamic Conquests of the 7th and 8th Centuries CE. Either way, it isn't very clear. A great many plagues and pandemics (A greek word meaning "pan"-all and "demos"-people) swept through the ancient world between 1100 BCE and the 3rd Century CE, it is unknown if any of them were caused by the poxvirus. (Li, Carroll, Gardner, Walsh, Vitalis, Damon. 2007)
What is known is that by the 16th Century CE, Smallpox had virtually taken over Europe. Until then the trend was to have periods of large-scale infection followed by long dormant periods. However by the 16th Century, Europe had fully recovered from the Black Death and more people were living in large urban cities. During the late 15th and early 16th centuries Europeans had their first large scale contact with the Native peoples of the Western Hemisphere. The pandemics that would sweep through the American continent would devastate the native populations over the following 400 years. Smallpox was a disease that would claim 80-90% of those who were infected in the New World. (Li, Carroll, Gardner, Walsh, Vitalis, Damon. 2007)
Smallpox in the late 18th Century became endemic to every corner of the globe except Australia. Having no geographic restrictions, it spread quickly from person to person. In the final years of that Century an estimated 400,000 people died to the disease annually, including five reigning Monarchs. Around this time Variolation became a common treatment for wealthy citizens in Great Britain, its Colonies, and China. Although the practice would not be wide spread until the mid-19th Century, limited vaccination would help lessen the impact of the virus. The vast majority of Smallpox cases in the Western Hemisphere and Great Britain were V. minor, a significantly less deadly version of the Pox virus.
It spread quickly because its victims usually only suffered from mild systemic illness and were usually not incapacitated. Infection from V. minor would also provide resistance to the more deadly form of V. major. (Li, Carroll, Gardner, Walsh, Vitalis, Damon. 2007)
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| Distribution of Smallpox c1950s (Image from CDC Smallpox Zones, 1955) |
Monday, May 2, 2011
Bibliography
Albert MR, Ostheimer KG, Liewehr DJ, Steinberg SM, Breman JG. 2002. Smallpox manifestations and survival during the Boston epidemic of 1901 to 1903. Annals of Internal Medicine. 137(12): 993-1000.
Babkin IV, Shchelkunov SN. 2006. Time scale of Poxvirus evolution. Molecular Biology. 40(1): 16-19.
Cunha BE. 2004. Monkeypox in the United States: An occupational health look at the first cases. AAOHN Journal. 52(4): 164-168.
de Souza Trindade G, Drumond BP, et al. 2007. Zoonotic Vaccinia virus infection in Brazil: Clinical description and implications for health professionals. Journal of Clinical Microbiology. 45(4): 1370-1372.
Firth C, Kitchen A, Shapiro B, Suchard MA, Holmes EC, Rambaut A. 2010. Using time-structured data to estimate evolutionary rates of double-stranded DNA viruses. Molecular Biology and Evolution. 27(9): 2038-2051.
Image from Centers for Disease Control and Prevention. Smallpox zones 1955. http://globalhealthchronicles.org/smallpox/record/view/pid/emory:15tk6
Li Y, Carroll DS, Gardner SN, Walsh MC, Vitalis EA, Damon IK. 2007. On the origin of smallpox: Correlating variola phylogenics with historical smallpox records. PNAS. 104(40): 15787-15792.
Nesse R, Williams G. 1998. Evolution and the origins of disease. Scientific American. 279(5): 86-93.
Past pandemics that ravaged Europe [Internet] c7 November 2005, 20:36 GMT. UK. BBC News: [cited 2011 May 1] Available from: http://news.bbc.co.uk/2/hi/health/4381924.stm
Questions and Answers About Smallpox Disease [Internet]. c2009. Atlanta (GA): Centers for Disease
Control and Prevention: [cited 2011 May 2]. Available from: http://emergency.cdc.gov/agent/smallpox/faq/smallpox_disease.asp.
Rubins KH, Hensley LE, Jahrling PB, Whitney AR, et al. 2004. The host response to smallpox: Analysis of the gene expression program in peripheral blood cells in a nonhuman primate model. PNAS. 101(42): 15190-15195.
Shchelkunov SN. 2011. Evasion of mammalian defense systems by orthopoxviruses. Molecular Biology. 45(1): 24-35.
Smallpox Disease Images [Internet]. n.d. Atlanta (GA): Centers for Disease
Control and Prevention: [cited 2011 May 2]. Available from: http://emergency.cdc.gov/agent/smallpox/smallpoximages.asp.
Smallpox Disease Overview [Internet]. c2004. Atlanta (GA): Centers for Disease
Control and Prevention: [cited 2011 May 2]. Available from: http://emergency.cdc.gov/agent/smallpox/overview/disease-facts.asp.
Principles of Darwinian Medicine
Principle: “Virulence is a trait of the pathogen that can increase as well as decrease” (Nesse and Williams 1998).
People who had been vaccinated or “had been vaccinated within 3 weeks of admission [to the hospital]” were more likely to survive a Smallpox infection than those who had never been vaccinated (Albert et al. 2002). Vaccinated people could and did still get sick with Smallpox and show symptoms, however the disease was much less severe than in a patient who had not been vaccinated. Therefore in a population of vaccinated people, the Smallpox disease was less virulent, likely because it was more easily wiped out by the body’s immune system. (Albert et al. 2002)
Principle: “Symptoms of infection can benefit the pathogen, the host, both or neither” (Nesse and Williams 1998).
The high fever that occurs before the emergence of the rash and again before scabbing is the body trying to kill the virus. However, this symptom can kill the host as well, which obviously would not be beneficial. The sores that develop on the tongue and in the mouth and later break open are mainly beneficial to the virus. Once the sores break open, fresh virus may spread throughout the host or be passed on to a new host, carried on the breath and in the saliva of the infected host. The rash that forms during a Smallpox infection is the body’s way of trying to push the virus out through the skin. This is meant to benefit the human host, though it is painful and the pus from the pustules can actually transfer the virus to a new host, which would benefit the virus. (Smallpox Disease Overview 2004)
Principle: “Each disease needs a proximate explanation… as well as an evolutionary explanation of why members of the species are vulnerable to it” (Nesse and Williams 1998).
The proximate explanation of why humans catch Smallpox is that when exposed to an infected person, the virus will jump to a new host to replicate.
The evolutionary explanation of why humans are vulnerable to smallpox is probably related to the rise of agriculture and domesticated animals. Variola virus evolved from a rodent-borne Orthopoxvirus. This virus was carried by rodents that were attracted to the abundant food sources that could be found once humans began farming. At some point the virus jumped to humans and the domesticated animals they kept in close contact with. The Variola virus then specialized to humans, while others (such as cowpox) remained zoonotic, capable of jumping between species. (Pearce-Duvet 2006)
Principle: “Specific clinical recommendations must be based on clinical studies; clinical interventions based only on theory are not scientifically grounded and may cause harm” (Nesse and Williams 1998).
Firth et al. used scientific experimentation to determine the speed of replication and evolution for the Smallpox virus (VARV). Since VARV has double-stranded DNA, the previous assumption was that it replicates slower than viruses with single-stranded DNA and therefore would be easier to prevent, treat, or eradicate before a new strain evolved. What Firth et al. actually discovered is that VARV evolves at a much higher rate than was previously assumed. This kind of data is important to understand before doctors attempt to control a disease, because moving with the assumption that the disease evolves slowly when the opposite is true could have disastrous results. (Firth et al. 2010)
Biology of Smallpox
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| Pustules on a smallpox-infected boy. (Smallpox Disease Images, n.d.) |
Smallpox is an infectious disease caused by the Variola virus of the genus Orthopoxvirus. There are two strains; the more common and more severe is Variola major; the less common and less severe is Variola minor. V. major can cause four forms of illness: ordinary, which accounts for about 90% of cases; modified, which is a mild version of “ordinary” and occurs when previously vaccinated people get Smallpox; and flat and hemorrhagic, which are both very rare and very severe forms. V. minor is less severe than V. major and only has death rates of 1% or less. Humans are the only known host of the variola virus. (Smallpox Disease Overview 2004)
Any form of Smallpox may be fatal, but overall the death rate is as high as 30%, according to the CDC (Questions and Answers 2009).
Smallpox is most often spread directly from person to person by contact or through contact with infected bodily fluids. It may be spread less directly through contact with items that have become contaminated, such as clothing. Smallpox rarely spreads through the air. (Questions and Answers 2009)
A Smallpox case may last 29-41 days if the infected person survives. There is an incubation period of about 7 to 17 days, during which time people are not contagious. The first symptoms are a high fever, aching, and vomiting; these usually leave people too sick to move around and last for 2 to 4 days. After this comes a rash that starts on the tongue and in the mouth but spreads all over the body, concentrating on the head and legs. The most contagious point is when the sores in the mouth burst open, spreading the virus into the mouth and throat. About 24 hours after the rash appears, the fever drops and the person may begin feeling well. The rash will raise into bumps by the third day and by the fourth those bumps fill with pus. At this point the fever returns and remains high until scabbing occurs. Around the fifth day after the rash appears, the bumps become round and hard (pustules). About five days after the formation of the pustules, they begin to scab. Most sores will be scabs by 14 days after the appearance of the rash. Once the pustules scab, they begin to fall off. As the scabs fall off, they leave scars on the skin. Most scabs fall off about a week after they form. Until all the scabs have fallen off, a person is still considered contagious. (Smallpox Disease Overview 2004)
Though there is no treatment for Smallpox, there is evidence that vaccination within the first 4 days of exposure “could abort or significantly reduce the severity of Smallpox disease” (Questions and Answers 2009).
Prevention includes getting a vaccination and avoiding infected people. However, the vaccination does not provide lifelong immunity, and the first vaccination has the side effect of a rash that is similar to, but should not be confused with, the rash resulting from Smallpox disease. (Questions and Answers 2009). |
| Comparison of rash clustering on a smallpox patient and a chickenpox patient. (Smallpox Disease Overview, 2004) |
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