Syphilis

Question 1

Etiology and Epidemiology of Syphilis:

1. What was it originally called? What regions was it endemic to?
2. How has this disease had a major impact on human culture?

Answer 1

1. originally called the great pox, spread through Europe in the 1490’s, reached China by the early 1500’s, then recurrent epidemics in the east and west into the 18th century
2. Major impact on public health, showed the culture of disease transmission (STIs), art/literature

Question 2

What impact did Treponema have on society and culture?

Answer 2

• large impact on art and culture
• “stages of mending a face”, by Rowlandson, illustration, cartoon of a prostitute with late stage syphilis, hair loss was a symptom of the disease
• Saddle nose of de lairesse, by Rembrant

Question 3

Explain how Pariahs were treated in society.

1. What stage of the disease was this?
2. What did in cause in the patients face?
3. Is this stage of the disease contagious?
4. What are some of the explanations for these disfigurements?

Answer 3

1. this was the late stage of the disease, the tertiary stage
2. caused disfigurement of the face,
3. this stage of the disease is not contagious
4. the disfigurement of syphilis is a consequence of the granulomatous nature of latent infection, akin to Tuberculosis, attacks tissues in the neck and in the face, mostly oral/nasal cavities
   
   • congenital syphilis: tooth and bone deformations in nasal septum, vertically transmitted intrapartum
   • venereal syphilis: classic STI, nodules on head/chest, form of the skin/bones.organs, are highly destructive

Question 4

Origins of Syphilis:

1. Who were the people who contributed to the discovery of Syphilis?
2. What did they find out about the disease?
3. What were some early treatments for T.pallidum?

Answer 4

1. Fritz Schaudinn, a German Protozoologist, and Erich Hoffmann, a German Dermatologist, are associated with the discovery of association of Treponema pallidum with syphilis, connected the dots to see that they are associated with each other, TP is the idioloic agent
2. they were able to demonstrate spirochetes in Giemsa-stained smears of fluid, taken form a syphilitic lesion
3. “One night with Venus, the rest of life with mercury”, this saying was in reference to an early treatment to syphilis, taking compounds of mercury, the treatment was taken to halt the disease before its secondary/tertiary form, this way of treating is highly toxic, patients say that the treatment of the disease is worse than the disease itself

Question 5

Origins of Syphilis:

What were some early treatments for T.pallidum?

Answer 5

• “One night with Venus, the rest of life with mercury”, this saying was in reference to an early treatment to syphilis,
• taking compounds of mercury, the treatment was taken to halt the disease before its secondary/tertiary form,
• this way of treating is highly toxic, patients say that the treatment of the disease is worse than the disease itself
• other treatments include:
  
  • use of organic arsenical compounds
  • bismuth
  • salvarsan
  • penicillin in the 1940’s

Question 6

Taxonomy if Syphilis:

1. What types of diseases are in the genus Treponema?
2. What are the species that are associated with acute disease?
3. Where does the non-pathogenic form of the disease reside?

Answer 6

1. the genus, Treponema, contains both pathogenic and non-pathogenic species, at least 20 in total
2. species of interest: T.pallidum and T,carateum are the major human pathogens
3. non-pathogenic species tend to be native to the GI tract/ genitourinary tract, humans and non-humans symbiosis

Question 7

Describe the morphology of Treponema:

Answer 7

• helical, corkscrew-shaped cells, spirochetes
• PCM, up to 15nm
• causative agent of Borrelia and Leptospira, other members of spirochetes
• those that have been characterized [spirochetes] can cause disease in humans
• Causative agent of syphilis, the spirochete, T.pallidum

Question 8

Answer these questions about the epidemiology of Syphilis:

1. What is the source of T.pallidum infection? Are there non-human reservoirs? How many people are infected each year?
2. What is the primary mode of transmission for syphilis? Infection rates for venereal syphilis?
3. What are the CFR’s for untreated syphilis? What other infections does T.pallidum cause?

Answer 8

1. humans are the only source for T.pallidum infection, THIS IS NOT TRUE THERE ARE SOME NON-HUMAN RESERVOIRS
   
   • there are no known non-human reservoirs
   • venereal syphilis- approx. 10 million cases/year
2. primary mode of transmission is sexual contact [STI;direct]
   
   • congenital syphilis is caused by vertical transmission
   • infection rates for venereal syphilis correspond w/the most sexually active groups, 20-24 year olds
3. left untreated CFR’s are as high as 60%
   
   • T.pallidum causes endemic syphilis and yaws, these 2 diseases have a different epidemiology/pathosis than venereal syphilis

Question 9

Answer these questions about the epidemiology of Syphilis:
1. Venereal syphilis is characterized by what cycles of infection? What do those cycles mean? Can latent T.pallidum be reactivated after exposure?

Answer 9

1. venereal syphilis- both acute and latent cycles of infection
   
   • Acute: includes both primary and secondary phases, both within 0-5/6 months
   • Latent infection: can happen over decades, can lead to various phase 3 syndromes [tertiary], these syndromes are life threatening, involve the skin, bones, organs [cardiovascular system], central nervous system, 6 months and over (like 30 years into the future)

Question 10

Answer these questions about the epidemiology of Syphilis:

1. What are some ways the incidence of syphilis infections can be reduced in the human population?
2. What 2 versions of T.pallidum is endemic to the tropics?

Answer 10

1. syphilis can be significantly reduces by surveillance of the disease, changes in sexual behavior, with introduction of penicillin (antibiotic chemotherapy), education on STI’s, decreased the total/overall incidences of syphilis
2. Yaws and Pinta remain endemic in the tropics, Pinta- Mexico/South America, Yaws- Africa, Bejel- West Africa/Middle east, another name for endemic T.pallidum

Question 11

Describe the Structural components of Syphilis, Cellular envelope:

1. Trepomena has a unique cell envelope. What is unique about the cell envelope?
2. What is the non-reactivity associated with?
3. What is the significance of cardiolipin?

Answer 11

1. while considered to be gram-negative(similar architecture) , they are generally non-reactive, meaning they do not elicit immunity, and they have no LPS, non-reactive stealth envelope
   
   • as a result of not having any LPS present, they are essentially invisible to our immune system, if there is nothing antigenic on the cell, then there will be no immune response
2. believed to be a result form the paucity of the outer membrane associated proteins
3. lipid chemistry of outer/inner proteins is also unique, there is a high density of cardiolipin, this is serologically used as a diagnostic tool
   
   • cardiolipin generally accumulates in bacterial membranes in response to stressors

Question 12

Syphilis as a stealth pathogen:

1. Because of the lack of OMPs in the outer membrane of T.pallidum, what is displayed?

Answer 12

1. intact T.pallidum, they display limited immunoreactivity (OM lability), may protect the pathogen from the immune system (during latency)
   
   • lack of outer membrane proteins and lack of limited immmunoreactivity
   • lysis exposes antigens that are reactive, structural quirk of these pathogens, the flagella is intracellular, the flagella are inside the cell and protected form the host, referred to as endo-flagella

Question 13

Describe the motility of Syphilis:

1. Is Treponema highly motile? What does it consist of?
2. What about the flagella of Treponema?

Answer 13

1. they are highly motile, they consist of rapid rotation about its longitudinal axis, bending, flexing, snapping
2. the flagella in T.pallidum is intracellular, hidden under the surface of the cell

Question 14

Describe the Endoflagella of T.pal:

1. Where is the flagella in T.pallidum located? Where is it extended?
2. How is motility achieved in T.pallidum?

Answer 14

1. they are located in the periplasmic space
   
   • extended along the axis of the pathogen, like OMPs it hides the flagella, apart of its stealth approach to pathogenesis
2. motility is achieved by rotation of flagella along the axis of the cell in the periplasmic space
   
   • Ex: the endoflagella is along the axis, it is hidden under the OM, EX: locomotion by rotation around the axis

Question 15

Answer these questions about Trepanematoses:

1. What are the 4 treponematoses caused by Treponema?
2. What are Syphilis, Yaws and Bejel caused by?
3. What is Pinta caused by?

Answer 15

1. venereal syphilis, pallidum
   
   1. 2 yaws, pertenue
   2. 3 endemic syphilis, Bejel, endemicum
   3. 4 pinta
2. caused by the subspecies T.pallidum
3. caused by the species T.carateum

Question 16

Explain Yaws:

1. What is it an infection of? Where is it specific to?
2. How is it transmitted?
3. What percentage of the population has Yaws in some of these regions?
4. Why is it called YAWS and what is the significance of the lesions?

Answer 16

1. it is an infection of the joints, skin, bones, it is endemic to Africa and South America, the tropics, highly destructive, can lead to cavitation/gumitis disease
2. it is transmitted via direct contact with lesions, non-STI, that is to say it is not transmitted via sexual means
3. in endemic regions, there is 75% contract YAWS before the age of 20, 50 mill cases per year
   
   • note that late stages of the disease, it is non-infectious, the early stages of the disease are more infectious and infection to another person is more likely to happen during the primary stages of the disease
4. The term YAWS comes from the word YaYa- translates to “painful sore”, direct transmission happens via contact with YAWS sores,
   
   • early stage disease, develop during the first few weeks @ site of entry,
   • at first is is a papuloid that later developed to a cluster of ulcers(YAWS),
   • first Yaw to form is called the mother YAW, the lesions have treponema, T.pallidum

Question 17

Answer these questions about Bejel and Pinta:

1. Where are Bejel and Pinta endemic to?
2. How are they transmitted?
3. Are they similar to YAWS? What about the late stage of the diseases?
4. When does Bejel tend to happen within a person and what are the clinical syndromes showed?

Answer 17

1. both diseases are endemic to the Middle East, tropical regions
2. both are primary transmitted by direct contact, non-STI, with lesions, that is to say it is not transmitted via sexual transmission
3. symptoms similar to yaws, late stages are characterized by gammas in the bone and soft tissue, very destructive to tissues and bone
4. very common in childhood (Bejel), ulcers forming in the mouth and spreading to the limbs

Question 18

Answer these questions about venereal syphilis: slide 25-30

1. What are the clinical manifestations of syphilis?
2. What does primary syphilis present as?
3. What do these chancres contain?

Answer 18

1. clinical manifestations are generally complex, periods associated with each stage vary greatly, is an STI, involvement in the genitourinary tract
2. primary syphilis presents as an acute prodromic(early symptom) ulceration (chancre) @ the site on infection (genitals), more visable/common in men
3. they contain hoards of tremonems (the bacteria)
   
   • the chancre is very contagious

Question 19

Answer these questions about venereal syphilis:

1. What are some of the syndromes that let you know you are @ the secondary stage of the disease?
2. At this stage is it highly contagious? What specific part is highly contagious?

Answer 19

1. onset of secondary stage, may occur months later, disseminated maculopapular rash and generalized lymphadenopathy
2. yes this stage is highly contagious, patches and plaques appear on mucous membranes, mouth and intestines, all lesions are highly contagious
   
   • the pox (maculopapular rash) are a hallmark symptom of the secondary phase of the disease

Question 20

Answer these questions about venereal syphilis:

1. Explain the significance of the latency between the secondary and tertiary periods of disease for syphilis.
2. In latent syphilis, what percentage of latent syphilis (secondary), lead to tertiary syphilis? What are the complications that come with this stage of syphilis?
3. What is the significance of the tertiary phase of syphilis?

Answer 20

1. the period of time between the secondary and tertiary phases of the disease can last for many years, this occurs in the spleen and the lymphatics
2. 28% of people with secondary syphilis develop tertiary syphilis, (recurrence of secondary syphilis symptoms in up to 25% of individuals)
   
   • complications can arise form these symptoms, gumma, cardiovascular syphilis, late neurological complications
   • 72% of the time the body will clear the infections and there will be no complications
3. tertiary disease can target almost any tissue, most fatalities (80%) are attributed to cardiovascular syphilis
   
   • gummas are narcotizing gramolomas

Question 21

Nercotizing granulomas:

1. What stage does this happen?
2. What happens to the face in this stage?
3. Is it contagious @ this stage? Is the role in pathogenesis known?

Answer 21

1. this happens during the tertiary stage of the disease
2. it generally occurs in the skin and in he soft tissue/bones,
   
   • immunopathologic response are from the gummas and have little/no role in transmission and little/no role in the fitness of the pathogen,
   • they are just collateral damage,
   • very little you can do for the patient
3. it is not very contagious at this stage but it is very destructive, it contains Very few T.pallidum, its role in pathogenesis is unknown

Question 22

Answer these questions about T.pallidum:

1. How is transmitted to the fetus?
2. When is disease progression accelerated?
3. What is tertiary congenital syphilis associated with? What are the clinical manifestations for this?

Answer 22

1. T.pallidum can be vertically transmitted to the fetus and will result in a 50% chance that the baby will be a stillborn, differences in pediatric immunity
2. the disease progression happens with accelerated congenital disease
3. tertiary disease is associated with diverse syphilitic clinical manifestations
   
   • blindness, tooth deformation, bone deformation of the legs, nasal septum(saddle nose) and hard palate

Question 23

Explain the pathogenesis of T.pallidum:

1. Why have the determinants of pathogenesis been elusive in T.pallidum?
2. [][][] slide 31

Answer 23

1. pathogenesis is elusive because there is a lack of cultivability and lack of an animal model
   
   • comparative genomics has revealed few canonical virulence factors

Question 24

Answer these questions about Treponema virulence:
1. What is the virulence of Treponema determined by?
2. In vitro studies using various tissues, what happens?
slide 32

Answer 24

1. it is determined by its ability for dissemination and immune evasion
2. in vitro, diff. tissue types show broad tissue tropism that is consistent with its isolation from the blood, CNS, liver, lymph, skin, spleen
   
   • dissemination in the blood/lymphatics has been estimated to occur within hours of exposure

Question 25

Answer these questions about virulence factors in T.pallidum:

1. What do putative virulence factors include?
2. What is the central latency of T.pallidum?
3. Tissue damage and death results from what? slide 33

Answer 25

1. include glycosidase, hyaluronidase, the adherence factor (?), pallilysin, endoflagella
2. the ability to evade immune detection
3. results form invasion and replication in the CNS (central nervous system) and cardiovascular system

Question 26

Answer these questions about Pallilysin:

1. T.pallidum disseminated hematologically to do what?
2. How is the adherence factor, pallilysin, used by T.pallidum? slide 34

Answer 26

1. to invade various tissues, connective and epithelial, and organs, CNS, kidney, spleen, oral cavity
2. it is used to colonize the endothelial lining of blood vessels preceding cellular transmigration

Question 27

Answer these questions about the adherence factor, pallilysin:

1. What is the function of Pallilysin? What does it slow and how does it do this?
2. What does intimate attachment lead to?
3. What are the 3 stages in order? slide 35

Answer 27

1. it slows T.pallidum in vasculature. How does it do this?
   
   • It binds to the EMC proteins, then,
   • intimately interacts with endothelial cell receptors
     
     • EX: cells lining blood and lymphatic vessels
2. it leads to paracellular invasion
3. Step 1) ECM binding, Step 2) Endothelial cell receptor binding, Step 3) Extravasion of the host epithelium

Question 28

Invasion of Endothelial Cells:

1. What does T.pallidum do to start invasion? How does it leave the circulation?
2. Where does it travel? slide 36

Answer 28

1. it can rapidly penetrate between circular tight junctions in endothelial cells, it leaves the circulation via peracellular traversal
2. it leaves via paracellular traversal in order to access deeper tissues

Question 29

Paracellular invasion in T.pallidum:

1. In paracellular invasion, T.pallidum does what to rabbit endothelial cells?
2. How does the corkscrew shape help T.pallidum? slide 37

Answer 29

1. it invades intercellular junctions of the rabbit endothelial cells
2. the corkscrew shape and motility, helps facilitate the mechanism, Paracellular invasion

Question 30

Hyaluronidase in T.pallidum:

1. What does T.pallidum produce hyaluronidase, HAse, for? Is it used by other integumental pathogens?
2. HAse is a glycoside used to do what?
3. Where is Hyaluronan abundant in? slides 38-39

Answer 30

1. for dissemination in connective and epithelial tissues, HAse is produced
   
   • yes, it is produce in other pathogens, Staphylococcus, S.pyogenes, C.perfringens
2. used to degrade glycosaminoglycans, GAGs, such as hyaluronan
3. most abundant in connective, epithelial, and neurologic tissues

Question 31

Diagnosis and Therapy and Prevention:

1. Why is the diagnosis of syphilis difficult? As a result, what must be relied on for a diagnosis?
2. Where does the dark field microscopy come from?
3. What are some of the serologic test used to diagnose syphilis? slide 40

Answer 31

1. complicated by the inability to culture in vitro, rely on 1. disease manifestation, 2. microscopy of treponemes in lesions, 3. serology
   
   • also not well developed in animal models
   • case history and clinical presentation are important
2. comes from exudate
3. Cardiolipin and protein antigens serological tests

Question 32

RPR Test:

1. What type of test is it?
2. What does it measure?
3. How is it derived? slide 41

Answer 32

1. it is a primary agglutination test
2. it measures the IgG levels in the blood to lipids (cardiolipin)
3. the host is T.pallidum and host derived

Question 33

FTA-ABS test:

1. What does the test use and what is it specific for?
2. What does it confirm?

Answer 33

1. the test used serum

2. it confirms RPR screening

Question 34

Answer these questions about prevention of syphilis:

1. What can be done for prevention?
2. What can be done from and educational standpoint?
3. Can there be trace contacts of syphilis?
4. Is there a vaccine for T.pallidum?

Answer 34

1. abstinence and prophylactics are the most effective method
2. education regarding the primary symptoms of syphilis (chancre, lesions), seek treatment during highly contagious stages of the disease
3. trace contact patients w/syphilis before inset of disease
4. There is very little success for a vaccine

Question 35

Therapy for syphilis:

1. What antibiotics can be used for treatment?
2. Are the drugs effective against YAWS, Pinta, endemic syphilis?

Answer 35

1. penicillin is the first like antibiotic, both for primary and secondary syphilis, also tetracycline
2. yes, these drugs are effective against those diseases