Where did syphilis come from?

Some infectious agents, it seems, have been with us since the rise of humanity. Bacteria like E. coli or salmonella don't appear to have one moment enshrined in history where they first appeared on the scene. They've probably long been with us, causing disease sporadically but not spectacularly.

Other agents, however, seem to make their presence known. Syphilis is one of these. The first recorded outbreaks of syphilis (caused by the bacterium Treponema pallidum subspecies pallidum) were documented in Europe in 1495. These weren't syphilis as we know it today. Currently, syphilis is a sexually-transmitted infection that typically has 3 phases of disease. Primary syphilis is the initial phase, characterized by perhaps a lesion on the genitalia. This typically resolves on its own, and the patient may either get better or progress to secondary syphilis. Secondary syphilis is characterized by a distinctive rash, which is fairly unique in that it is present not only on the usual areas of the body (typically the extremities for this rash), but also presents on the palms of the hands and soles of the feet. This feature could be diagnostic, but it's not always present. Infection progresses to the secondary phase generally weeks to months after the primary symptoms.

Tertiary syphilis is the final phase of the disease, and the most difficult to diagnose on symptoms alone. There can be neurological involvement, leading to the "madness" of syphilis; or it can attack the cardiovascular system or the digestive system, leading to heart failure or painful bowel problems that can last for years. Tertiary syphilis is not only insidious in its diverse array of symptoms, but also in its lag time from initial infection: as little as one year, or as many as 50. The disease is a complex and often mysterious one.

However, just as mysterious has been the origin of T. pallidum. As I mentioned, the disease we see today bears little resemblance to syphilis when it was first recognized in Europe during the late 15th century. At this point, syphilis wasn't a hidden venereal disease: it was a highly virulent infection that could run its course in a matter of weeks to months, covering the victim in sores from head to toe until they died an excruciating death. However, this highly pathogenic form was soon replaced with a milder version of the disease, more similar to what we see today.

But a larger question looms: where did syphilis come from? It's widely agreed upon by scholars that syphilis appears to be a "new" disease to Europeans at this point in history--so had it been hiding in another reservoir prior to this time? Did a new subspecies emerge from older, related infections? Or did the voyages of Columbus bring this microbe back to the Old World from the New? There have been a number of conflicting publications on this over the past several years (and indeed, the debate is as old as Columbus' voyages themselves), with archaeological evidence and that from microbiology sometimes coming into conflict regarding the origin and evolution of subspecies of Treponema pallidum. A new study swings it back to Columbus, suggesting that Treponema pallidum likely has its origin in the New World. More after the jump...

In addition to the subspecies of Treponema that causes syphilis, there are other species that cause disease in humans, typically in tropical areas. Treponema pallidum subspecies pertenue causes a disease called yaws, a spirochete infection transmitted generally via direct skin contact that can cause bone deformity and disfigurement. Bejel ("endemic syphilis") is caused by another subspecies of T. pallidum, but is transmitted typically from mouth-to-mouth contact rather than venereal spread, and most common in Mediterranean countries. Treponema pallidum subspecies carateum causes the final Treponemal disease, pinta--a similar skin disease found in parts of Mexico and Central and South America.

Figuring out the relationship between these diseases--and which affected human populations when--has been an active area of investigation for many years. Much of this research has focused on evidence from bones, which show characteristic signs of infection with syphilis and the related diseases. The controversy has revolved around whether bones have been found in Europe which show signs characteristic of syphilis that can be dated to pre-Columbian times. For many years, no pre-Columbian skeletal remains showing signs characteristic of syphilis had been uncovered in Europe. However, an announcement in 2000 suggested that such a find had been discovered, throwing doubt on the Columbian origin of syphilis. The controversy has been an active one in the past several years.

This new study examines not bones, but modern isolates of the Treponema subspecies: 26 samples, including isolates taken from cases of yaws and bejel (in addition to diagnosed syphilis patients) as well as animal (baboon and rabbit) isolates. These isolates were examined at 21 loci around the genome, and the sequence data was used to construct a phylogeny. From this they suggest that the subspecies pertenue (which causes yaws) is the most ancient subspecies, and is related to organisms found in other primates (which they suggest may have been the initial source of infection). At the opposite end of the spectrum, the syphilis spirochete appears to be the most recently diverged, and appeared to have also diverged from Old World yaws strains in what they suggest could have been a 3-stage evolution:

First, T. pallidum arose in the Old World, in the form of non-venereal infection, before spreading with humans to the Middle East/Eastern Europe, in the form of endemic syphilis, and then to the Americas, in the form of New World yaws. Second, a T. pallidum strain from the Americas was introduced back into the Old World, probably as a result of the European exploration of the Americas, becoming the progenitor of modern syphilis-causing strains. Third, modern subsp. pallidum strains disseminated from Europe to the rest of the world.

So, is this the end to the controversy? Far from it. First, as the authors acknowledge, their study is only as good as their collection of strains. They note that the non-venereal strains have dramatically decreased in prevalence, so that entire element is lost for analysis. Additionally, most of the syphilis isolates were largely represented by New World strains, while the endemicum and pertenue isolates were mostly Old World--so what they ended up with in their analysis may simply be reflecting geographic distances. Additional strains are really needed, but difficult to obtain (especially since Treponema still is resistant to traditional culture methods).

They also note that their study could answer some questions, but raise others:

The virtual absence of syphilitic lesions from Pre-Columbian Old World skeletons can be explained simply in the context of this data; syphilis did not exist in these areas until the Renaissance. On the other hand, the absence of lesions typical of yaws or endemic syphilis in these areas is puzzling in light of the genetic data. If the non-venereal treponematoses arose in the Old World long before syphilis, then why isn't there more evidence of their presence? If yaws was the first form of treponemal disease, as indicated by our study, and was limited to hot, humid areas, we would expect preservation of ancient, affected remains to be poor. This may contribute to the paucity of skeletal finds.

An interesting paper, but certainly not the last word in this area. It will be interesting to see more DNA sequencing approaches of ancient tissues, to see what they come up with, and whether those support the pre- or post-Columbian origin of syphilis in Europe.

References

Harper KN et al. 2008. On the Origin of the Treponematoses: A Phylogenetic Approach. PLoS Neglected Tropical Disease. Link.

Mulligan et al 2008. Molecular Studies in Treponema pallidum Evolution: Toward Clarity? PLoS Neglected Tropical Disease. Link.

Image from http://blogs.jobdig.com/wwds/files/2007/05/older-columbus.gif