Syphilis is a sexually transmitted infection that is caused by the spirochetes bacterium Treponema pallidum subsp. pallidum. T. pallidum belongs to a family of spiral-shaped bacteria, the Spirochaetaceae (spirochete), and is related to other pathogenic treponemes that cause nonvenereal disease, that is diseases contracted or transmitted via sexual contact (LaFond & Lukehart, 2006). Treponemes stain poorly with aniline dyes (Rodolf); however, spirochetes tend to be gram- negative. Because of how thin T. pallidum is, it is difficult to classify its gram stain (Baron, 1996). The coiled shaped body of T. pallidum is surrounded by a cytoplasmic membrane, which is enclosed by a loose outer membrane. A thin later of peptidoglycan between these membranes provides structural stability (LaFond & Lukehart, 2006).
T. pallidum lacks certain metabolic capabilities. The organism has the ability to carry out glycolysis, but lacks tricarboxylic acid cycle enzymes and an electronic transport chain. It also lacks components of oxidative phosphorylation and most biosynthetic pathways, relying on the host to perform necessary functions (Cameron & Lukehart, 2013; Fantry & Tramont, n.d. ;LaFond & Lukehart, 2006). T. pallidum cannot survive out of the mammalian host. This inability of T. pallidum to survive and multiply outside the mammalian host is the greatest barriers to syphilis research (LaFond & Lukehart, 2006). The generation time of T. pallidum is relatively slow; inoculation studies show that T. pallidum doubles every 30 to 33 hours inside the body of the mammalian host (LaFond & Lukehart, 2006). Several biological factors contribute to T. pallidum’s slow generation rate. Because glycolysis is the only metabolic pathway that T. Pallidum can carry out, it is solely dependent upon this pathway for ATP synthesis (LaFond & Lukehart, 2006). These factors, along with T. pallidum’s limited heat tolerance and oxygen sensitivity are all factors that may possibly hinder the replication of T. pallidum. Despite these factors, T. Pallidum quickly causes chronic infection and varied disease manifestations in the host.
T. Pallidum lacks lipopolysaccharide (LPS), the endotoxin found in the outer membranes of many gram- negative bacteria that causes fever and inflammation; however, T. Pallidum does produce a number of lipoproteins which may induce the expression of inflammatory mediators via toll-like receptor 2 (TLR2) recognition (LaFond & Lukehart, 2006). Humans are first infected with syphilis at the genital and anal areas of the body. Humans can also be infected with syphilis through the oral cavity and nongenital dermal sites; however, infections at these sites are fairly rare and are clear indications that organisms widely scatter from the initial site of contact (LaFond & Lukehart, 2006). Just like any other bacterial pathogen, the first step in T. pallidum invasion is the attachment of organisms to the host cells. T. pallidum has been shown to attach to a variety of cell types including epithelial, fibroblastlike, and endothelial cells (LaFond & Lukehart, 2006).
Migrating bacteria are dependent upon chemotactic responses to move toward preferred environments and away from hostile environments (LaFond & Lukehart, 2006). The distribution of motile bacterial pathogens in tissues may be facilitated by chemotaxis (LaFond & Lukehart, 2006). Methyl accepting chemotaxis transmembrane proteins (MCPs) and cytoplasmic chemotaxis proteins (Che) make up the chemotaxis system of gram- negative bacteria, and T. pallidum has similar proteins for each of these systems (LaFond & Lukehart, 2006). Four genes for MCPs are found in the T. pallidum genome. MCPs sense attractants and repellants in the environment; glucose and histidine are molecules that may have affinity for T. pallidum MCPs (LaFond & Lukehart, 2006). Two operons in the T. pallidum genome contain genes for the Che response regulators. Pathogenic processes such as crossing the endothelial barrier in order to reach the bloodstream are likely to depend upon mechanisms that allow T. pallidum to sense and respond to nutrient gradients (LaFond & Lukehart, 2006).
During bacterial infection, endothelial cells, dendritic cell, and macrophages recognize shared microbial patterns such as LPS, peptidoglycan, and the acyl subdivisions of lipoproteins (LaFond & Lukehart, 2006). This recognition is interceded by receptors, the TLRs, found on the cells surface. In many bacterial infections, the immature dendritic cells, at the site of infection, take up the bacteria. These dendritic cells migrate to the lymph notes, where they activate T- cells. As they mature, the dendritic cells produce inflammatory cytokines in response to pathogenic stimulation.
Endothelial cell activation and migration of inflammatory cells are further augmented by the secretion of soluble immune factors called cytokines (LaFond & Lukehart, 2006). Exposure to intact and sonicated T. pallidum induces macrophages to express TNF- α, a cytokine that activates a number of components of the immune response (LaFond & Lukehart, 2006). Stimulation of macrophages by purified T. pallidum lipopeptides, or with representative synthetic lipopeptides, also induces expression of the proinflammatory cytokines (LaFond & Lukehart, 2006). TpN47 activates the expression of TNF-α, IL-β, IL-6, IL-8, and IL12 (LaFond & Lukehart, 2006). TNF-α production is also induced by TpN15, TpN17, and TpN38. The stimulation of the macrophage cell lines with TpN17 and activates IL-β production (LaFond & Lukehart, 2006). TpN47 induces expression of the T-cell chemoattractant cytokines MIP-1α and MIP-1β (LaFond & Lukehart, 2006). Liver macrophages called Kupffer cells also produce TNF-α in response to stimulation with the whole T. pallidum organisms or with the lipoproteins TpN47, TpN15, TpN15, and TmpA (LaFond & Lukehart, 2006). These findings indicate that T. pallidum lipoproteins are effective inducers of inflammation during the early stages of syphilis infection.
Dendritic cells act as antigen presenting cells to T-cells in the lymph nodes. T- cells induced in the response to syphilis infection are highly reactive to several of the major T. pallidum proteins, including TpN47, TpN17, and TpN15- lipoproteins embedded in the outer leaflet of the cytoplasmic membrane- and TpN37, TpN35, TpN33, and TpN30- proteins that make up the core and sheath of the T. pallidum flagella (LaFond & Lukehart, 2006). In response to cytokine signals from the T- cells, macrophages migrate to the site of infection, are activated by interferon IFN-γ, and ingest and kill the organisms. The complement protein C3b makes the pathogen recognizable to macrophages by specific cell surface receptors. In macrophage recognition of T. pallidum, opsonization is accomplished by antibodies IgG and IgM (LaFond & Lukehart, 2006). T. pallidum antigens, including Tp92 and TprK, have been shown to induce the production of opsonic antibodies (LaFond & Lukehart, 2006). Antibodies against the VDRL (Venereal Disease Research Laboratory) antigen, a complex of cardiolipin, cholesterol, and lecithin, also increase the phagocytosis of T. pallidum by macrophages (LaFond & Lukehart, 2006).
T. pallidum invades a number of anatomical sites, including the central nervous system, eye, and placenta, tissues that may be “immune privileged” in that less surveillance by the innate immune system may occur in those sites (LaFond & Lukehart, 2006). An important defense mechanism used by the host is iron seclusion. The host iron-binding proteins transferrin and lactoferrin cause free iron to be unavailable to bacteria, impairing their growth. T. pallidum interacts with both transferrin and lactoferrin, and the organism may be able to obtain iron from these host proteins (LaFond & Lukehart, 2006). It is hypothesized that a minimum number of organisms is required to trigger host response. By maintaining infection with few organisms in anatomical sites distant from one another, T. pallidum may prevent its clearance by failing to alert the immune response to its presence (LaFond & Lukehart, 2006).
Penicillin is the drug of choice in treating syphilis. Several T. pallidum proteins have been shown to bind to penicillin (LaFond & Lukehart, 2006). Penicillin kills the bacterium by interfering with the production of the cell wall (LaFond & Lukehart, 2006). The most reliable treatment for any form of syphilis in any type patients in 3-4 million units of aqueous crystalline penicillin G give intravenously (IV) every 4 hours (12-24 million units daily) for 10-14 days (LaFond & Lukehart, 2006).
In the case of a penicillin allergy, doxycycline or tetracycline is used as a form of alternative treatment (LaFond & Lukehart, 2006). In the 1990’s, azithromycin emerged as yet another alternative to penicillin. Early syphilis has been shown to be successfully treated with just a single dose of azithromycin (LaFond & Lukehart, 2006).
The vast majority of syphilis cases are transmitted via sexual contact or from an infected pregnant woman to her fetus (LaFond & Lukehart, 2006; Stamm, 2010). Persons are most infectious in early stages of the disease and by 4 years after acquiring the disease, an untreated immunocompetent person is essentially non-infectious (LaFond & Lukehart, 2006). The prevalence of this disease is greatest in the South Eastern U.S., urban areas, among African Americans, and in persons with lower and less education (Fantry & Tramont, n.d.;LaFond & Lukehart, 2006). Infectivity rates correspond to the most sexually active age groups, being highest in the 20-24 year age group (Radolf, 1996).
While the widespread epidemics of syphilis that occurred in Russia in the 1990s and more recently China involved mostly heterosexuals, smaller outbreaks in the U.S., Canada, and England largely involve homosexual, sexually active men (Fantry & Tramont, n.d.;Stamm, 2010). There was steady decline in the number of syphilis cases in both Europe and the U.S. during the second half of the last century; however, recent increases in syphilis rates for U.S. women and infants suggest that heterosexually transmitted syphilis may be a growing problem in the U.S. (Fantry & Tramont, n.d.; Lynn & Lightman, 2004; Stamm, 2010). The reasons underlying recent increases include the migration of people from high-prevalence countries, population mixing, changes in risk behavior including the use of the Internet to meet partners, use of recreational drugs, and a reduction in safe sex practices in gay men (Lynn & Lightman, 2004).
Syphilis infections place individuals at a 2-5 fold enhanced risk for HIV transmission. The health cost of potentially preventable HIV infections was estimated at $113 million (Lynn & Lightman, 2004). Modeling studies have shown that effective syphilis control would have a significant impact on HIV prevention. The global public health threat posed by syphilis proves the need for a better understanding of syphilis pathogenesis and identification of possible vaccine targets (Cameron & Lukehart, 2013; Fantry & Tramont, n.d.; Lynn & Lightman, 2004; Stamm, 2010). The growing number of cases reflects social factors such as changing sexual habits, trading sex for drugs, and rising rates of pregnancy among teenagers who do not use contraceptives. The symptoms of syphilis also have the ability to negatively impact social life, especially relationships and marriage, considering the path of transmission that this disease takes. Because syphilis is transmitted via sexual contact, it is in a classification of diseases that are viewed more negatively by society than any other classification.

References
Cameron, C. E., & Lukehart, S. A. (2013). Current Status of Syphilis Vaccine Development: Need, Challenges, Prospects. Vaccine, 32(14), 1602–1609. doi:10.1016/j.vaccine.2013.09.053
Fantry, L., & Tramont, E. (n.d.). Treponema Pallidum (Syphilis).
LaFond, R., & Lukehart, S. (2006). Biological Basis for Syphilis. Clinical Microbiology Reviews, 19(1), 29-43. doi:10.1128/CMR.19.1.29–49.2006
Lynn, W., & Lightman, S. (2004). Syphilis and HIV: A dangerous combination. The Lancet, 4, 456-466.
Radolf, J. (1996). Treponema. In Medical Microbiology (4th ed.). Galveston, TX.: University of Texas Medical Branch at Galveston.
Stamm, L. (2010). Global Challenge of Antibiotic-Resistant Treponema pallidum. Antimicrobial Agents And Chemotherapy, 54(2), 583-589. doi:10.1128/AAC.01095-09