Notes
Treponema (Syphilis)
Sections
Subspecies of Treponema pallidum cause Syphilis, Yaws, and Bejel (also known as endemic syphilis).
Spirochetes have a spiral, or corkscrew shape.
Microaerophilic, which means they require low oxygen concentration.
Rely on the host to meet their nutritional requirements, and are very difficult to culture.
Very thin cell walls, which renders them invisible with Gram or Giemsa stains.
Darkfield microscopy or direct antibody fluorescent antibody tests are used to visualize these bacteria.
Diagnosis of treponemal infection is achieved via serology, which typically includes a nontreponemal screening test followed by a treponemal test.
Pathophysiology:
Complex, and virulence factors and infectious mechanisms are not entirely understood.
Low toxicity
Highly invasive
– Flagellar motility
– Adhere to components of the extracellular matrix
The tissue destruction*associated with treponemal infection is thought to be caused by the host inflammatory response:
Bacterial release of lipoproteins recruits and activates immune cells, and lesions are characterized by infiltration of lymphocytes, macrophages, plasma cells, and granuloma formation.
Treponema evade the immune system - "stealth pathogen"
Resists phagocytosis and removal.
The bacteria have relatively few surface proteins and undergo antigenic variation, which inhibits recognition and removal by the host immune system.
Venereal syphilis
Caused by Treponema pallidum subspecies pallidum.
These bacteria have only human reservoirs, and are transmitted via sexual contact, the placenta, or via contaminated blood transfusion.
Primary phase is characterized by localized lesions, which manifest approximately 3-6 weeks after initial infection.
CD4+ T cells and macrophages predominate in the lesions, which typically present as painless chancres.
Regional lymphadenopathy is also common.
The chancres are highly infectious, and usually heal spontaneously within a couple of months; this may give the patient a false sense of security.
Secondary phase of syphilis is the result of bacterial dissemination, aka, bacteremia.
Approximately 6 weeks after infection, CD8+ T cells, which are cytotoxic, predominate.
Widespread maculopapular rash and lymphadenopathy with headache and malaise are common.
Patients may also have flu-like symptoms, including fever.
In some cases, condyloma lata develop; show that these knobby or wart-like lesions grow in skin folds, especially in the genital/anal regions.
Some individuals develop mucosal legions, particularly in the oral cavity.
Other organ systems may be affected, and patients can present with hepatic, pulmonary, neurologic, and ocular dysfunctions in the secondary phase of syphilis.
Secondary syphilis can resolve spontaneously.
Latent phase
Patients are usually asymptomatic during the latent stage, but relapse is common, and placental transmission is still possible.
Tertiary phase
Approximately 30% of untreated patients enter the Tertiary phase, which is characterized by complications that arise years, even decades, after initial infection.
Common complications:
Cardiovascular and neurological impairment.
Cardiovascular dysfunction is typically related to the aorta and coronary arteries.
Neurological dysfunction can include meningitis, ocular and cranial nerve impairment, focal deficits, tabes dorsalis (loss of corrdination), paresis, personality changes, and dementia.
Many of these neurologic complications are the result of vascular dysfunction and/or demyelination.
Gummas, which are benign, rubbery granulomas, can form in most organ systems; they are especially common in the bones and skin, but also form in the viscera and brain.
Congenital syphilis occurs when the bacteria cross the placenta and infect the fetus; infection often leads to spontaneous abortion or stillbirth, or, in live births, abnormal growth and development.
HIV co-infection
Syphilis increases the risk of HIV infection, although the exact mechanism is uncertain.
In co-infected patients, it seems that the diseases interact in ways that shape clinical outcomes. For example, co-infection seems to increase the risk of neurological complications.
Non-venereal treponemal diseases
Transmitted via non-sexual contact.
Yaws
Infection typically found in children in warm tropical areas.
Associated with Treponema pallidum subspecies pertenue.
Initial lesions are usually on the lower extremities, but, if the infection is untreated, can lead to more widespread destruction of skin and bone.
Endemic syphilis, aka, Bejel
Typically affects children living in hot, dry areas, such the Southern and Sahel regions of Africa.
It is caused by Treponema pallidum subspecies endemicum.
Initial lesions often arise in the oral mucosa; untreated infection causes destruction of skin and bones of the face.
Pinta
Infection more commonly found in adults.
It is caused by Treponema carateum.
The initial lesion is typically on the extremities; unlike yaws and endemic syphilis, pinta infection only affects the skin.
Penicillin & Jarish-Herxheimer reaction
Penicillin is the drug of choice.
However, be aware that some patients will experience a Jarish-Herxheimer reaction 4-16 hours after penicillin administration.
Once thought to be caused by an allergy, we know think the reaction is caused by the killing of the spirochetes.
In most cases, the reaction is nonfatal, and presents with chills, fever, myalgia, and rash.
In pregnant women, preterm uterine contractions can occur.
Changes in white blood cell count can be telling; look for leukocytosis and lymphopenia.
Be aware that more serious organ dysfunction, stroke, or seizures are possible.
Full-Length Text
Here we will learn about pathological species of Treponema, with a focus on Treponema pallidum.
To begin, indicate that subspecies of Treponema pallidum cause Syphilis, Yaws, and Bejel (also known as endemic syphilis).
Write that Treponema are Spirochetes; that is, they have a spiral, or corkscrew shape.
They are microaerophilic, which means they require low oxygen concentration.
Because they rely on the host to meet their nutritional requirements, they are very difficult to culture.
Treponema have very thin cell walls, which renders them invisible with Gram or Giemsa stains;
Darkfield microscopy or direct antibody fluorescent antibody tests are used to visualize these bacteria.
Diagnosis of treponemal infection is achieved via serology, which typically includes a nontreponemal screening test followed by a treponemal test.
The pathophysiology of Treponema pallidum is complex, and virulence factors and infectious mechanisms are not entirely understood.
Write that the bacteria have low toxicity, but that they are highly invasive, due to flagellar motility and the ability to adhere to components of the extracellular matrix.
The tissue destruction associated with treponemal infection is thought to be caused by the host inflammatory response:
Write that bacterial release of lipoproteins recruits and activates immune cells, and lesions are characterized by infiltration of lymphocytes, macrophages, plasma cells, and granuloma formation.
For the most part, however, the bacteria evade the immune system; Treponema pallidum has been called a "stealth pathogen" because it resists phagocytosis and removal.
For example, write that the bacteria have relatively few surface proteins and undergo antigenic variation, which inhibits recognition and removal by the host immune system.
Now, let's learn about diseases caused by Treponema.
We'll begin with venereal syphilis.
Write that it is caused by Treponema pallidum subspecies pallidum.
These bacteria have only human reservoirs, and are transmitted via sexual contact, the placenta, or via contaminated blood transfusion.
The natural history of syphilis is clinically divided into three phases.
Write that the primary phase is characterized by localized lesions, which manifest
approximately 3-6 weeks after initial infection.
CD4+ T cells and macrophages predominate in the lesions, which typically present as painless chancres; regional lymphadenopathy is also common.
The chancres are highly infectious, and usually heal spontaneously within a couple of months; this may give the patient a false sense of security.
The secondary phase of syphilis is the result of bacterial dissemination, aka, bacteremia.
Approximately 6 weeks after infection, CD8+ T cells, which are cytotoxic, predominate.
Show that a widespread maculopapular rash and lymphadenopathy with headache and malaise are common.
Patients may also have flu-like symptoms, including fever.
In some cases, condyloma lata develop; show that these knobby or wart-like lesions grow in skin folds, especially in the genital/anal regions.
And, some individuals develop mucosal legions, particularly in the oral cavity.
Write that other organ systems may be affected, and patients can present with hepatic, pulmonary, neurologic, and ocular dysfunctions in the secondary phase of syphilis.
Secondary syphilis can resolve spontaneously.
Patients are usually asymptomatic during the latent stage, but relapse is common, and placental transmission is still possible.
Next, indicate that approximately 30% of untreated patients enter the Tertiary phase, which is characterized by complications that arise years, even decades, after initial infection.
Common complications include cardiovascular and neurological impairment.
Write that the cardiovascular dysfunction is typically related to the aorta and coronary arteries.
Neurological dysfunction can include meningitis, ocular and cranial nerve impairment, focal deficits, tabes dorsalis (loss of corrdination), paresis, personality changes, and dementia.
Many of these neurologic complications are the result of vascular dysfunction and/or demyelination.
Lastly, write that gummas, which are benign, rubbery granulomas, can form in most organ systems; they are especially common in the bones and skin, but also form in the viscera and brain.
Congenital syphilis occurs when the bacteria cross the placenta and infect the fetus; infection often leads to spontaneous abortion or stillbirth, or, in live births, abnormal growth and development.
Write that syphilis increases the risk of HIV infection, although the exact mechanism is uncertain.
In co-infected patients, it seems that the diseases interact in ways that shape clinical outcomes. For example, co-infection seems to increase the risk of neurological complications.
Next, let's consider key non-venereal treponemal diseases, which are transmitted via non-sexual contact.
First, write that yaws is an infection typically found in children in warm tropical areas; it is associated with Treponema pallidum subspecies pertenue.
Initial lesions are usually on the lower extremities, but, if the infection is untreated, can lead to more widespread destruction of skin and bone.
Endemic syphilis, aka, Bejel, typically affects children living in hot, dry areas, such the Southern and Sahel regions of Africa.
It is caused by Treponema pallidum subspecies endemicum.
Initial lesions often arise in the oral mucosa; untreated infection causes destruction of skin and bones of the face.
Pinta is an infection more commonly found in adults; it is caused by Treponema carateum.
The initial lesion is typically on the extremities; unlike yaws and endemic syphilis, pinta infection only affects the skin.
Finally, let's consider treatment of treponemal diseases.
Penicillin is the drug of choice.
However, be aware that some patients will experience a Jarish-Herxheimer reaction 4-16 hours after penicillin administration. Once thought to be caused by an allergy, we know think the reaction is caused by the killing of the spirochetes.
In most cases, the reaction is nonfatal, and presents with chills, fever, myalgia, and rash.
In pregnant women, preterm uterine contractions can occur.
Changes in white blood cell count can be telling; look for leukocytosis and lymphopenia.
Be aware that more serious organ dysfunction, stroke, or seizures are possible.
References:
Murray, P. R., Rosenthal, K. S., & Pfaller, M. A. Medical microbiology. Philadelphia: Elsevier/Saunders. (2013).
Levinson, W. E. Review of Medical Microbiology and Immunology. 14th Ed. Lange (2016).
Kestelyn, P. (2010). Venereal and Endemic Treponematoses in the Developing World. International Ophthalmology Clinics. 50(2): 41-55.
Marks, M., Solomon, A.W., Mabey, D.C. (2014). Endemic treponemal diseases. Trans R Soc Trop Med Hyg. 108:601–607.
Mitja, O., Smajs, D., Bassat, Q. (2013). Advances in the Diagnosis of Endemic Treponematoses: Yaws, Bejel, and Pinta. PLOS Neglected Tropical Diseases. 7(10): e2283.
Salazar, J.C., Cruz, A.R., Pope, C.D., Valderrama, L., Trujillo, R., Saravia, N.G., Radolf, J.D. (2007). Treponema pallidum Elicits Innate
and Adaptive Cellular Immune Responses in Skin and Blood during Secondary Syphilis: A Flow-Cytometric Analysis. The Journal of Infectious Diseases. 195:879–87.
Butler, T. (2017). The Jarisch–Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. Am. J. Trop. Med. Hyg. 96(1):46–52.
Peeling, R.W. & Hook, E.W. (2006). The pathogenesis of syphilis: the Great Mimicker, revisited. J Pathol. 208: 224–232.
Cruz, A.R., Ramirez, L.G., Zuluaga, A.V., Pillay, A., Abreu, C., Valencia, C.A., et. al. (2012). Immune Evasion and Recognition of the Syphilis Spirochete in Blood and Skin of Secondary Syphilis Patients: Two Immunologically Distinct Compartments. 6(7): e1717.
Gianci, L., Brandt, S.L., Puray-Chavez, M., Reid, T.B., Godornes C., Molini, B.J., et al. (2012). Comparative Investigation of the Genomic Regions Involved in Antigenic Variation of the TprK Antigen among Treponemal Species, Subspecies, and Strains. Journal of Bacteriology. 194(16):4208–4225.
Lui, J., Howell, J.K., Bradley, S.D., Zheng, Y., Zhou, Z.H., Norris, S.J. (2010). Cellular Architecture of Treponema pallidum: Novel Flagellum,
Periplasmic Cone, and Cell Envelope as Revealed by Cryo-Electron Tomography. J Mol Biol. 403(4): 546–561.
Giacani, L., Molini, B.J., Kim, E.Y., Godornes, B.C., Leader, B.T., Tantalo, L.C., et al. Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis. J Immunol. 184(7): 3822–3829.
Images:
Treponema dark field microscopy (CDC/C.W. Hubbard).