The Origin - Etiology and Treatment of Syphilis

The Origin, Etiology and Treatment of Syphilis

"And this disease of which I speak, this syphilis too will pass away and die out, but later it will be born again and be seen again by our grandchildren just as in bygone ages we must believe it was observed by our ancestors." - Fracastoro, 1538 1

It has been written about, debated over, and has affected every culture it has come into contact with. One can only be amazed when examining the microscopic syphilis bacterium. It traveled the seas of 1492 with Columbus, fought alongside Hitler in the war of the worlds, and gambled with the likes of Al Capone. 2 This bacterium has been a part of hundreds of year's worth of human history, and probably thousands of year's worth of prehistory. Technology has enabled us to sequence the genome of syphilis, exposing every possible characteristic and genomic code function, yet no one knows where the bacterium calls home. Syphilis has revolutionized western medicine and our approach to public health, yet no vaccine has been developed. It is a mystery how historical evidence has shown the symptoms of the disease since the beginning of mankind, yet outbreaks still occur in modern time. By understanding the theories of origin, the morphological, genomic, and relative characteristics of the disease and its treatment, the riddle of this disease may be cracked in the near future.

Syphilis, the third most common sexually transmitted disease, affects 12 million new people each year and is the leading cause of stillbirths and deaths among newborns in many developing countries. 3 The causative agent of venereal syphilis is Treponema pallidum, under the Family Spirochaetaceae of the Order Spirochaetales. It is a spirochete, a helical to sinusoidal bacterium ranging from 5 to 15 microns in length. 2 T. pallidum multiplies by binary transverse fission and enter the body through mucous membranes (squamous or columnar epithelium cells) or minor breaks or abrasions in the skin. From there, it migrates to every corner of the body through the blood and lymphatic circulatory system, infecting virtually every bodily organ, including the nervous system. Infections can even reach the womb, infecting the newborn known as congenital syphilis .4

Despite its importance as an infectious agent, relatively little is known about T. pallidum in comparison with other bacteria. The genome of Treponema pallidum was sequenced in 1998 by the Institute for Genomic Research to show 1,138,006 base pairs with an average G + C content of 52.8%. There are a total of 1,041 predicted open reading frames, with an average size of 1,023 base pairs, representing 92.9% of total genomic DNA. 5 Comparison of the T. pallidum genome sequence with that of another pathogenic spirochete, Borrelia burgdorferi, the agent of Lyme disease, identified unique and common genes and substantiates through considerable diversity observed among pathogenic spirochetes. Furthermore, the gene sequence has indicated that a Gap1 sequence from T. pallidum is very closely related to GAPDH genes from the eukaryotic Euglenozoa, indicating that an interkingdom gene transfer may have occurred between these organisms. 6

The sequencing of the Treponema pallidum genome can also set itself apart from many non-pathogenic relatives. The first major difference is that syphilis has been hindered by the inability to culture the bacterium outside the human host. The reason for this is because scientists do not know the nutrition needed for the spirochete. 5 The second major difference revealed through gene sequencing is that the bacterium's metabolism is very limited. Absent from the spirochete are many biosynthetic pathways. Examples include pathways for synthesis of enzyme cofactors, fatty acids, nucleotides, and some electron transport proteins. Because of the limited biosynthetic capabilities, Treponema pallidum depends on the host for multiple nutrients. Thus, the spirochete has a repertoire of transport proteins with broad substrate specificity to obtain the necessary nutrients from the environment. The transport protein code takes up a significant 5% of the T. pallidum genome. The genome encodes 18 distinct transporters specified for amino acids, carbohydrates, and cations. 5

The consequential use of many protein transporters is the necessity of an adequate amount of energy. Contrasting from non-pathogenic relatives, Treponema pallidum lacks a TCA cycle. Rather, it uses carbohydrates such as glucose, galactose, maltose, and glycerol as an energy source. Phosphorylation within the T. pallidum is done by the usual hexokinase enzyme. However, instead of the typical eubacterial phosphofructokinase and pyruvate kinase, T. pallidum contains homologs of these enzymes that use pyrophosphate. In T. pallidum, the pyruvate kinase function is probably taken over by phosphoenolpyruvate synthase, which is capable of catalyzing pyruvate formation by reversing its typical reaction. Obtaining inorganic phosphate is also different from other relatives in that the spirochete uses a sugar transport instead of an uptake system. 5

Differing in structure from the enteric Gram-negative bacteria, Treponema pallidum contains both outer and cytoplasmic membranes. Unlike the Gram-negative bacteria, the peptidoglycan underlies the outer membrane and the murein layer overlies the cytoplasmic membrane. This layer gives Treponema pallidum a unique characteristic different from other spirochetes because it has few proteins exposed on the surface. Many believe the surface genes undergo recombination in order to generate new surface proteins, permitting the organism to evade the human immune response. Analysis of T. pallidum indicates the presence of only 22 putative surface lipoproteins, as compared with 105 in B. burgdorferi, consistent with results from ultrastructural studies. 6 The outer proteins of T. pallidum are also different from other bacterium in that the repeat protein K, a specific protein for syphilis of unknown function that appear to be important in the immune response during syphilitic infection. Experiments hint that repeat protein K give the bacterium an ability to evade the host immune responses and cause disease over a period of years to decades, hence the long latent and tertiary stages. 5 The motility of the spirochete also has unique characteristics not seen in other bacteria.

In 1936, the active movement of venereal syphilis was studied by Dr. Wm. A. Hinton of Boston. It was during these studies that Dr. Hinton found a unique morphological property of the T. pallidum not seen in any other bacterium: the axial filament. Dr. Hinton observed that the motility of the T. Pallidum is somewhat characteristic and has been aptly described as that of an animated corkscrew. He noted that the organisms move chiefly in the direction