DEFINITION
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum.It has been known as "the great imitator" due to its frequent atypical presentations.The tipical presentation it depends on which of the four stages it presents (primary, secondary, latent, and tertiary). The primary stage classically presents with a single chancre (a firm, painless, non-itchy skin ulceration), secondary syphilis with a diffuse rash which frequently involves the palms of the hands and soles of the feet, latent syphilis with little to no symptoms, and tertiary syphilis with gummas(pathology), neurological, or cardiac symptoms. Untreated, it has a mortality of 8% to 58%, with a greater death rate in males.
EPIDEMIOLOGY
The WHO has estimated that 12 million new cases of venereal syphilis occurred in 1999, most of them in developing countries. Congenital syphilis remains a leading cause of perinatal and neonatal deaths in many developing countries. In countries undergoing social upheaval such as Russia and much of Eastern Europe, the re-emergence of syphilis is a contributor to burgeoning HIV epidemics. In North America and Western Europe, where the disease is less common, syphilis epidemiology has shifted to become disproportionately common because of increased promiscuity, prostitution, decreasing use of barrier protection or persons using cocaine and other drugs.
MORPHOLOGY of Treponema pallidum
T. pallidum subsp. Pallidum belongs to a family of spiral-shaped bacteria, theSpirochaetaceae (spirochetes), and is related to other pathogenic treponemes that cause nonvenereal diseases.
T. pallidum varies from 6 to 15 μm in length and is 0.2 μm in diameter. In both clinical and laboratory settings, dark-field microscopy is used for visualization of this small organism. The spiral-shaped body of T. pallidum is surrounded by a cytoplasmic membrane, which is enclosed by a loosely associated outer membrane. A thin layer of peptidoglycan between the membranes provides structural stability. Endoflagella, organelles that allow for the characteristic corkscrew motility of T. pallidum, are located in the periplasmic space.
BACTERIOLOGY
Treponema pallidum subspecies pallidum is a spiral-shaped, Gram-negative, highly mobile bacterium with limited metabolic capacity. The organism is able to carry out glycolysis but lacks tricarboxylic acid cycle enzymes,electron transport chain and amino acid and fatty acid synthesis pathways; but T. pallidum does carry enzymes for the interconversion of amino acids and fatty acids. With this dearth of biosynthetic pathways, it is suspected that T. pallidum derives most essential macromolecules from the host, using interconversion pathways to generate others.
Because the T. pallidum genome encodes no known homologs to porin proteins, it is unclear how nutrients are moved across the outer membrane into the periplasmic space. A recent study suggests that Tp0453, a putative outer membrane protein, may perturb the outer membrane by insertion into its inner leaflet, allowing nonselective diffusion of nutrients into the periplasm.
Many efforts to elucidate molecular mechanisms of T. pallidum virulence have been hampered by certain characteristics of the organism.T. Pallidum (does not survive outside the mammalian host; infectious capability is lost within a few hours or days of harvest).
The generation time of T. pallidum is unusually slow. Inoculation studies determined that T. pallidum doubles every 30 to 33 h in vivo. Several biological factors may contribute to T. pallidum's sluggish replication rate. Because it lacks a tricarboxylic acid cycle and an electron transport chain, T. pallidum depends upon glycolysis as the sole pathway for the synthesis of ATP. In fact, the theoretical energy yield of an organism that undergoes aerobic respiration, such as E. coli, is 38 ATP, 19 times greater than the 2 ATP synthesized from glycolysis alone. E. coli doubles approximately every 20 min, at least 90 times faster than T. pallidum, suggesting that low energy production is not the only factor that inhibits T. pallidum replication.
In addition to its sensitivity to oxygen, T. pallidum may have a limited stress response, in facts it lacks of typical heat shock response ,reflecting the sensitivity of the organism to growth temperature. At least one T. pallidum enzyme is unstable at normal body temperature, suggesting that the heat lability of enzymes may also contribute to the slow growth of the organism. Heat therapy for late neurosyphilis was introduced in 1918 by the Viennese psychiatrist Julius Wagner von Jauregg. The regimen consisted of inoculating patients with malaria-infected blood and, 10 to 12 febrile episodes later, treating them with quinine. The high temperatures induced by this regimen, along with other methods of raising body temperature that were later introduced, presumably killed T. pallidum in the CNS. Genetic intractability, related to the inability to grow the organism, is another hindrance to T. pallidum molecular research. Unlike the related spirochetesTreponema denticola and B. burgdorferi, no system for genetic manipulation of T. pallidum yet exists. Because of the fragility of its outer membrane, genetic manipulation of T. pallidum may prove impossible.
PATHOGENESIS
T. pallidum is a helically shaped micro-aerophilic bacterium, 6–20 µm in length and 0.10 – 0.18 µm in diameter. It consists of a central protoplasmic cylinder bounded by a cytoplasmic membrane, an overlying layer of peptidoglycan, and an outer membrane. Motility is conferred by two to three flagella, which originate at each end of the organism. The outer membraneof T. pallidum does not contain lipopolysaccharide and has relatively few surface-exposed transmembrane proteins.
The lack of outer membrane immune targets has led to T. pallidum being labelled as a stealth pathogen. Although not much is known about the rare membrane proteins of T. pallidum, they have the potential to be virulence determinants and at least one of them has been shown to be a porin Recent studies have identified a family of T. pallidum repeat genes, the tpr genes, which encode proteins that mediate attachment to host tissue, and function as porins. The Tpr proteins are immunogenic in rabbits. Antigenic variation through gene conversion in infection has been hypothesized to be another mechanism by which the organism avoids host immune response, allowing for prolonged infection and persistence in the presence of a robust host response. Similar mechanisms have been described for spirochetes of the genus Borrelia, which cause relapsing fever.Putative treponemal ligands that bind host fibronectin have been characterized by peptide mapping. An antibody raised against one of the protein fragments inhibited T. pallidum host cytadherence. Despite a striking lack of metabolic capabilities, sensitivity to oxygen, and decreased viability in an environment warmer than body temperature, T. pallidumis able to invade and survive in a wide variety of tissues and organs. The diverse manifestations of human syphilis also demonstrate the invasiveness of T. pallidum. Humans are initially infected with syphilis at anogenital and, more rarely, oral and nongenital dermal sites, yet the rash of secondary syphilis is a clear indication that organisms disseminate widely from the primary site of contact. T. pallidum has been detected directly in tissues and fluids far from the initial site of infection. Using PCR and infectivity testing, T. pallidum is routinely found in the CSF (cerebro-spinal fluid) of individuals with early and latent syphilis. T. pallidum has been detected decades after initial infection in tertiary gummatous lesions of the skin. In the face of a hostile host environment and a strong specific immune response, there are several mechanisms that the organism might use to ensure its continued existence in the host.
T. pallidum penetrates a broad variety 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. Organisms may survive in these tissues, slowly replicating and possibly reseeding other tissues.
T. pallidum may prevent its clearance by failing to alert the immune response to its presence. In this scenario, T. pallidum may spend months to years in a quiescent environment, with organisms dividing very slowly. Indeed, it is quite likely that T. pallidum undergoes an even lower rate of division during latent disease, as late latent syphilis must be treated by a prolonged course of penicillin to prevent treatment failure. Unknown factors cause T. pallidum to begin dividing at a higher rate again in certain anatomical areas in a small percentage of individuals, leading to symptomatic late syphilis.
An important defense mechanism utilized by the host is iron sequestration. The host iron-binding proteins transferrin and lactoferrin cause free iron to be unavailable to bacteria, impairing their growth. T. pallidum has been reported to interact with both transferrin and lactoferrin and the organism may be able to acquire iron from these host proteins. T. pallidum may also overcome host iron sequestration by utilizing enzymes that bind metals other than iron. Unlike many bacterial pathogens, T. pallidum lacks an electron transport chain, which is made up of enzymes that use iron as a cofactor, and T. pallidum appears to have very few other enzymes or components that require iron. A regulated system for the uptake of metals such as zinc and manganese has been described, suggesting that these metals may act as iron alternatives.In the absence of cytotoxins and other known virulence factors, it is probable that inflammation and the ensuing adaptive immune response to T. pallidum cause the tissue destruction characteristic of syphilis infection.
T. pallidum quickly gains access to deeper tissues and the bloodstream, probably by traversing the junctions between endothelial cells inducing the production of matrix metalloproteinase.
The presence of a pathogen signals inflammatory and immune cells to migrate from the bloodstream to the site of infection. An early step in this homing mechanism is the expression of cell adhesion molecules (ICAM-1, VCAM-1, and E-selectin) on capillary endothelial cells, promoting the leakage of serous fluids and the migration of leukocytes out of blood vessels into infected tissues. Virulent T. pallidum induces cultured endothelial cells to express the adhesion molecules. During acute bacterial infection, polymorphonuclear lymphocytes (PMNs) are often the first cells to infiltrate the site of infection. PMNs are seen in very early syphilis lesions that are experimentally induced and naturally acquired, although infiltration is transient and the number of PMNs is low relative to that seen in other acute bacterial infections. The inability of PMNs to adequately control T. pallidum is demonstrated by the progression of infection following this mild localized early inflammatory response.
During bacterial infection, endothelial cells, dendritic cells, and macrophages recognize shared microbial patterns such as LPS, peptidoglycan, and the acylated moieties of lipoproteins. This recognition is mediated by receptors, the TLRs, found on the cell surface.
Dendritic CellsDendritic cells (DCs) are stimulated by microbial lipopeptides through the TLR2 pathway. Specialized DCs called Langerhans cells are found in skin, the site of the majority of primary and secondary lesions; DCs are also found in the mucosa, the intestinal wall, and the heart, all potential sites of T. pallidum infection. In many bacterial infections, the bacteria are taken up by immature DCs at the site of infection, and the DCs then migrate to lymph nodes where they activate T cells. Specific T. pallidum molecules that have been shown to stimulate DCs are not surface localized, so the initiation of lipoprotein signaling of DCs is not likely to occur until the organisms are being degraded, exposing the lipoproteins to the TLR2 receptors. A delay in DC maturation, resulting in a slower inflammatory response, could allow the early dissemination of T. pallidum, giving organisms the opportunity to penetrate organs and tissues before an active inflammatory response has been mounted by the host.
DCs act as a bridge between innate and adaptive immunity by presenting specific antigens to T cells in the lymph nodes, stimulating them to differentiate and migrate to the site of infection where they perform their specialized functions. Macrophages also infiltrate the site of infection after 6 to 10 days and reach maximal numbers at approximately day 13. Similarly, T cells and macrophages are found in human primary chancres and secondary lesions. In macrophage recognition of T. pallidum, opsonization is accomplished by antibodies, both immunoglobulin G (IgG) and IgM .
T. pallidum antigens have been shown to induce production of opsonic antibodies.
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 .
Antibodies in Syphilis ImmunityIgM antibodies are usually the first to develop after establishment of bacterial infection, followed shortly by IgG. Specific IgM continues to be produced in infected humans, even after disease symptoms have subsided, suggesting that exposure to T. pallidum antigens continually stimulates B cells. IgG persists throughout late latent syphilis in humans.
The antibody response elicited during infection is specific for a broad range of T. pallidum molecules, including lipids found on the surface of T. pallidum, flagellar proteins, lipoproteins, and various other proteins, including the Tprs.
Besides opsonization, there are other functions of antibodies produced during T. pallidum infection. Antiserum from T. pallidum-infected rabbits, presumably the IgG component, has been shown to block organisms from binding to cells in vitro, suggesting that attachment to host cells is mediated by treponemal adhesin molecules. In the presence of complement, anti-T. Pallidum antibodies immobilize organisms and neutralize the ability of the organisms to produce typical dermal lesions, but specific antibody alone is not sufficient to kill T. pallidum and prevent infection.
Some organisms survive in infected hosts despite the presence of strongly reactive antibodies directed against a number of T. pallidum proteins and activated T cells and macrophages in lesions. Outer surfaces are the first bacterial component to encounter the host and are often the targets of host adaptive immunity. Early researchers noted that antibodies in serum from infected animals
did not readily bind to intact treponemes, in facts only those treponemes that had been
physically disrupted reacted with anti-T. Pallidum antiserum, suggesting that the surface of T. pallidum is nonantigenic.
Most bacteria with a double membrane have a peptidoglycan layer that is linked to the outer membrane by lipoprotein molecules, but in T. pallidum peptidoglycan is thought to associate with the more abundant inner membrane proteins. Additionally,T. Pallidum lacks LPS , molecule that lends structural stability to bacterial outer membranes.
Several genes that encode candidate outer membrane proteins belong to the Tpr gene family. The twelve tpr genes are divided into three subfamilies. ThetprC, tprD, tprF, and tprI genes belong to subfamily I; tprE, tprG, and tprJbelong to subfamily II; and tprA, tprB, tprH, tprK, and tprL belong to subfamily III. Antibody responses arise at different times after infection: anti-TprK antibodies are seen as soon as 17 days postinfection and are robustly reactive at day 30, while antibodies against the members of subfamilies I and II often are not detectable until 45 days after infection and reach peak titers at day 60. The time of development of antibodies to specific Tprs may reveal the timing of expression of the proteins that induced those antibodies. Regulation of expression of related proteins is referred to as phase variation and may be utilized by T. pallidum to
down-regulate the expression of those Tprs against which an immune response has been mounted, while simultaneously up-regulating the expression of new Tprs. The expression of new proteins that are not recognized by the existing immune response may help T. pallidum maintain chronic infection. The TprK protein elicits both cellular and humoral immunity in infected animals.
Habitat and Portal of Entry
Humans are the only known natural reservoir for subspecies pallidum. It is unable to survive without a host for more than a few days. This is due to its small genome (1.14 MDa) and thus its inability to make most of its macronutrients. It has a slow doubling time of greater than 30 hours.The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting incongenital syphilis.
Mode of Transmission
Syphilis is passed from person to person through direct contactwith a syphilis sore. Sores occur mainly on the external genitals,vagina, anus, or in the rectum. Sores also can occur on the lips and in the mouth. Transmission of the organism occurs during vaginal, anal, or oral sex. Pregnant women with the disease can pass it to the babies they are carrying. Syphilis cannot be spread through contact with toilet seats, doorknobs, swimming pools, hot tubs, bathtubs, shared clothing, or eating utensils. Syphilis cannot be contracted through toilet seats, daily activities, hot tubs, or sharing eating utensils or clothing.
SIGNS and SYMPTOMS
Syphilis it is has often been called “the great imitator”:http://www.ncbi.nlm.nih.gov/pubmed/16362988 because so many of the signs and symptoms are indistinguishable from those of other diseases.Many people infected with syphilis do not have any symptomsfor years, yet remain at risk for late complications if they are not treated. Although transmission occurs from persons with sores who are in the primary or secondary stage, many of these sores are unrecognized. Thus, transmission may occur from persons who are unaware of their infection.
Primary Stage:
The primary stage of syphilis is usually marked by the appearance of a single sore (called a chancre), but there may be multiple sores. The time between infection with syphilis and the start of the first symptom can range from 10 to 90 days (average 21 days). The chancre is usuallyfirm, round, small, and painless. It appears at the spot where syphilis entered the body. The chancre lasts 3 to 6 weeks, and it heals without treatment. However, if adequate treatment is not administered, the infection progresses to the secondary stage.
Secondary Stage:
Skin rash and mucous membrane lesions characterize the secondary stage. This stage typically starts with the development of a rash on one or more areas of the body. The rash usually does not cause itching. Rashes associated with secondary syphilis can appear as the chancreis healing or several weeks after the chancre has healed. The characteristic rash of secondary syphilis may appear as rough, red, or reddish brown spots both on the palms of the hands and the bottoms of the feet. However, rashes with a different appearance may occur on other parts of the body, sometimes resembling rashes caused by other diseases. Sometimes rashes associated with secondary syphilis are so faint that they are not noticed. In addition to rashes, symptomsof secondary syphilis may include fever, swollen lymph glands, sore throat, patchy hair loss, headaches, weight loss, muscle aches, and fatigue. The signs and symptoms of secondary syphilis will resolve with or without treatment, but without treatment, the infection will progress to the latent and possibly late stages of disease.
Latent Stages:
The latent (hidden) stage of syphilis begins when primary and secondary symptoms disappear. Without treatment, the infected person will continue to have syphilis even though there are no signs or symptoms; infection remains in the body. This latent stage can last for years.
Tertiary Stage
Tertiary syphilis may occur approximately three to 15 years after the initial infection, and may be divided into three different forms: gummatous syphilis (15%), late neurosyphilis (6.5%), and cardiovascular syphilis (10%). Without treatment, a third of infected people develop tertiary disease.
Gummatous syphilis or late benign syphilis usually occurs one to 46 years after the initial infection, with an average of 15 years. This stage is characterized by the formation of chronic gummas, which are soft, tumor-like balls of inflammation which may vary considerably in size. They typically affect the skin, bone, and liver, but can occur anywhere.
Neurosyphilis refers to an infection involving the central nervous system. It may occur early, being either asymptomatic or in the form of syphilitic meningitis, or late as meningovascular syphilis, general paresis, or tabes dorsalis, which is associated with poor balance and lightning pains in the lower extremities. Late neurosyphilis typically occurs four to 25 years after the initial infection. Meningovascular syphilis typically presents with apathy and seizure, and general paresis with dementia and tabes dorsalis.
DIAGNOSIS
The antibodies produced in response to syphilis infection are exploited by clinicians for diagnostic purposes. The first serologic test for syphilis, developed in the early 20th century, was the Wasserman test. This test is classified as nontreponemal because the antigen, comprised of lecithin, cholesterol, and cardiolipin, is not unique to T. pallidum. These lipids are thought to be derived from the host and incorporated into the membrane of the metabolically limited T. pallidum, producing a configuration that is antigenic. Decades later, the antilipoidal antibody VDRL and rapid plasma reagin (RPR) tests were developed. Automation, antigen stability, the ability to use plasma rather than serum, and macroscopic observation make the RPR test more conducive for use in clinical laboratories. The VDRL test continues to be used in some settings, although it has no advantages over the RPR for diagnosis of syphilis.
The sensitivities of the RPR and VDRL syphilis diagnostic tests depend upon the stage of disease. In disease of short duration, i.e., when the primary chancre has just appeared, antilipoidal antibody tests are often negative; after several weeks of infection, however, the tests are usually positive. Accordingly, the mean sensitivities during primary syphilis of the RPR and VDRL tests are 86% and 78%, respectively, while the sensitivities of both tests during secondary syphilis are 100%. Antilipoidal antibody reactivity can arise as a result of tissue damage from recent or concurrent infectious diseases such as hepatitis or underlying autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus; these antibodies can cause a false-positive RPR or VDRL test. Because autoantibodies increase as a result of aging, elderly people are also at risk for a false-positive result.
TheT. pallidum immobilization (TPI) test, developed as a result of the discovery that serum from syphilis-infected patients inhibits treponemal mobility in the presence of active complement, was the first test to be specific for antitreponemal antibodies. Within a decade of its discovery, the TPI test was replaced by the more sensitive fluorescent treponemal antibody (FTA) test, later refined by an absorption step to the FTA-ABS test. These tests use anti-human Ig labeled with fluorescein to detect antibodies bound to T. pallidumorganisms on slides. Hemagglutination, a technically simpler test developed in the same era as the FTA-ABS test, detects reactive antibody that agglutinates red blood cells sensitized with T. pallidum antigen. The T. pallidum particle agglutination assay uses biologically inert gel particles in place of red blood cells and has fewer equivocal reactions than the hemagglutination test.To diagnose neurosyphilis, the CSF can also be tested for antibodies induced in response to infection withT. Pallidum (CFS-VDRL).
One antigen in particular, Tp0453, was shown to be highly sensitive in detecting infection during primary syphilis.
Dark ground microscopy of serous fluid from a chancre may be used to make an immediate diagnosis. However, hospitals do not always have equipment or experienced staff members, whereas testing must be done within 10 minutes of acquiring the sample. Sensitivity has been reported to be nearly 80%, thus can only be used to confirm a diagnosis but not rule one out.
PREVENTION
As of 2010, there is no vaccine effective for prevention. Abstinence from intimate physical contact with an infected person is effective at reducing the transmission of syphilis, as is the proper use of a latex condom. Condom use, however, does not completely eliminate the risk. Thus, the Centers for Disease Control and Prevention recommends a long-term, mutually monogamous relationship with an uninfected partner and the avoidance of substances such as alcohol and other drugs that increase risky sexual behavior. Congenital syphilis in the newborn can be prevented by screening mothers during early pregnancy and treating those who are infected. The World Health Organization recommends all women be tested at their first antenatal visit and again in the third trimester.
If they are positive, they recommend their partners also be treated. Congenital syphilis is, however, still common in the developing world, as many women do not receive antenatal care at all, and the antenatal care others do receive does not include screening, and it still occasionally occurs in the developed world, as those most likely to acquire syphilis (through drug use, etc.) are least likely to receive care during pregnancy.
MEDICAL MANAGEMENT
After 60 years of use, penicillin still remains the drug of choice in syphilis treatment. Several T. pallidum proteins have been shown to bind penicillin. Penicillin-binding proteins often function in cell wall synthesis pathways; thus, penicillin kills susceptible bacteria by interfering with production of cell walls. Recently, one penicillin-binding protein, TpN47, was shown to have β-lactamase activity; paradoxically, this activity is inhibited by the products of the reaction and the organism remains penicillin sensitive. Guidelines published by the Centers for Disease Control and Prevention specify oral doxycycline or tetracycline as alternative treatments in the case of penicillin allergy (except for pregnant women). Macrolide ResistanceIn the 1990s, azithromycin emerged as a particularly attractive alternative to penicillin therapy for syphilis . Azithromycin is given orally, in contrast to benzathine penicillin, which must be delivered intramuscularly in a large volume.
Early syphilis has been shown to be successfully treated with a single dose of azithromycin, and large azithromycin treatment trials are ongoing. In place with high rates of macrolide-resistant strains, penicillin should remain the drug of choice. In other place, certain situations may warrant the use of azithromycin to treat syphilis; however, to ensure efficacy of treatment, it is essential that patients be monitored carefully with clinical reevaluation and serological testing.
Syphilis infection increases the risk of transmitting and acquiring HIV infection. Not only are syphilis lesions a portal of entry for HIV but the immune cells that carry and are susceptible to the virus, macrophages and T lymphocytes, are found in abundance in syphilis lesions.
There is also some evidence for the direct involvement of T. pallidum in facilitating HIV
infection and progression.
Prevention of syphilis infections would help to stem the rising numbers of new HIV infections in the world and would certainly prevent congenital syphilis in developing nations. These issues, in addition to the possible serious late sequelae of untreated syphilis, provide a clear rationale for active syphilis vaccine development efforts.
